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"The study of metaphor is now firmly established as a central topic within cognitive science and the humanities. We marvel at the creative dexterity of gifted speakers and writers for their special talents in both thinking about certain ideas in new ways, and communicating these thoughts in vivid, poetic forms. Yet metaphors may not only be special communicative devices, but a fundamental part of everyday cognition in the form of 'conceptual metaphors'. An enormous body of empirical evidence from cognitive linguistics and related disciplines has emerged detailing how conceptual metaphors underlie significant aspects of language, thought, cultural and expressive action. Despite its influence and popularity, there have been major criticisms of conceptual metaphor. This book offers an evaluation of the arguments and empirical evidence for and against conceptual metaphors, much of which scholars on both sides of the wars fail to properly acknowledge"-- Provided by publisher.

When analyzing the results of diagnostic imaging studies, the radiologist traditionally makes reference to particular features representative of normality or pathology. Most of these features are associated with images of the world around us. This pictorial issue contains nearly 400 illustrations and descriptions of more than 100 classic radiological signs of chest and abdominal diseases that are not named after authors but based on metaphors derived from contemplation of our environment. By correlating the results of computed tomography with these vivid descriptive images, readers will be able to memorize typical and often pathognomonic patterns of disease more quickly and more easily. This book will be of value for both radiology residents and more experienced radiologists.

Presentation with advanced disease and distant recurrence following surgery typify pancreatic ductal adenocarcinoma (PDAC), underscoring the need for new treatments targeting metastasis in this cancer. Because elements of the immune system can both prevent and promote tumor progression, we studied the metastasis-associated immune response in PDAC models. We find that developing metastases are bordered by dense networks of CD11b+ dendritic cells (DC), which derive from monocytes exposed to tumor-released GM-CSF and drive Foxp3+ T regulatory cell (Treg) responses. Leveraging their selective expression of the C-type lectin MGL2, we show that depleting this DC population from metastatic tissues activates cytotoxic lymphocytes, reduces Tregs, and inhibits metastasis development. These DC also uniquely express PD-L2 in the metastatic microenvironment and thereby inhibit CD8 T cell-mediated antitumor immunity. Similar DC accumulate in PDAC tissues from other models and cancer patients, supporting the broad applicability of our findings. These results reveal that a specific DC subset both suppresses CD8 T cells and supports Tregs to create a microenvironment conducive to metastasis in pancreatic cancer. Targeting such immunosuppressive stromal cells represents a novel strategy for preventing the progression of this deadly disease.

"This IOM committee was formed at the request of the Bill & Melinda Gates Foundation and charged with addressing methodological challenges in late-stage nonvaccine biomedical HIV prevention trials with a specific focus on microbicide and pre-exposure prophylaxis trials."

One of the grand challenges in genomic medicine is to translate fundamental scientific discoveries regarding the structure, variation, and function of the genomes of individuals and populations towards improved health outcomes. The main hypothesis of this thesis is that all forms of human genetic variation contributing to the etiology and pathophysiology of modern human diseases have distinct and quantifiable evolutionary histories, which can be computed for every position in the human genome independent of human population characteristics, and used as informative quantitative priors in the discovery and assessment of variants of clinical importance in modern human populations. To enable robust evaluation of the specific questions posed by this thesis, I first explore the necessary properties and theoretical basis for a null evolutionary hypothesis for Evolutionary Genomic Medicine, and conclude that the well-established Neutral Theory of Molecular Evolution provides a sound theoretical and methodological basis for evaluating alternative hypothesis in Evolutionary Genomic Medicine. Due to advances in multiplex genotyping technologies, genome-wide associations studies (GWAS), have emerged as the premier modality for discovery and assessment clinical genomic variation. Although these efforts have been successful in revealing thousands variants robustly associated with a broad spectrum of clinical phenotypes, the variants established by the GWAS approach have so far failed to explain large proportions of the known genetic variance associated with important clinical traits such as Type 2 Diabetes and Hypertension. Because disease-associated variation is linked with genomic loci of functional importance which have undergone evolutionary selection, and even the proxy loci (e.g. tagging SNPs) used to probe for disease associated loci themselves have quantifiable evolutionary histories, I evaluate a compendium of disease-associated variants to evaluate the effect of long-term evolutionary histories on the discovery of disease-associated variants. Through this work I demonstrate that disease-associated variants have distinct evolutionary properties, and that evolutionary features of positions can be incorporated as priors to improve discovery of disease-associated variants. A similar approach is applied to evaluate pharmacogenomics variants associated with warfarin, demonstrating that evolutionary features of genomic positions improve clinical assessment of pharmacogenomics variation. Through the findings and insights gained from efforts in pursuit of my thesis which are reported here, my collaborators and I clearly demonstrate that quantitative evolutionary features can be estimated for each position in the human genome across species, and then applied to modern human population data to improve discovery and assessment of genomic variation associated with clinical phenotypes.

As outlined in the previous paper in this series (Riley et al., 2016), our nation needs foundational data in order to understand how social, physical, chemical, and nutritional environments interact to impact how Americans grow, live, and prosper. To satisfy this need, we propose a nationally representative birth cohort study beginning in the prenatal period and following the children through adulthood. Existing research efforts are in adequate because their data are not sufficiently comprehensive and representative to identify both positive and negative factors affecting children's health or to fully understand health inequities in the United States. A crucial element of the proposed study is a well-designed national probability sample from which conclusions can be drawn to the larger population from which the sample was randomly selected. In contrast, self-selection sampling consists of volunteers who elected to be part of a study. This technique introduces self-selection bias and can lead to a sample that is not representative of the population being studied. In fact, a report by the National Research Council (NRC) and the Institute of Medicine (IOM), The National Children's Study 2014: An Assessment, endorsed a probability sample design for a future national longitudinal birth cohort study (NRC/IOM, 2014; Riley et al., 2016). This paper provides an overview of a feasible sample design, methods for stakeholder engagement, tools for data collection, and approaches for providing access to the data that would maximize its value.

Most human variation lies outside of coding regions, where molecular functions are more difficult to determine than for variants in coding regions. As most disease-associated variants lie in non-coding regions, characterizing the role of regulatory variation is crucial to understanding the molecular mechanisms of these diseases and methods to do so are currently limited. Recently, a number of research efforts, including the ENCODE project, have produced a wealth of data on transcription factor binding sites and other regulatory information, in addition to increasingly available whole genome sequence and transcriptomics data. These data will crucial to understanding the molecular basis of many diseases, but their scale and disparate nature, as well as high levels of noise, require clever informatics methods to integrate and properly apply this information. In this thesis, I describe methods to address some of the major informatics challenges to characterize the role of regulatory variants in phenotypes and disease. In particular, I have shown that I can (1) detect cooperativity among transcription factors using human variation data, (2) associate transcription factors to functional modules and thus discover new TF interactions and disease associations, (3) provide molecular mechanisms for disease-associated non-coding variants, and (4) explore regulatory functional mechanisms using long-range interactions in the human genome.

"Effectiveness and Comparative Effectiveness Reviews, systematic reviews of existing research on the effectiveness, comparative effectiveness, and comparative harms of different medical tests, are intended to provide relevant evidence to inform real-world health care decisions for patients, providers, and policymakers. In an effort to improve the transparency, consistency, and scientific rigor of the work of the Effective Health Care (EHC) Program, the Agency for Healthcare Research and Quality (AHRQ), the Scientific Resource Center, and the Evidence-based Practice Centers (EPCs), have developed this Methods Guide for Medical Test Reviews (also referred to as the Medical Test Methods Guide). We intend it to serve as a resource for the EPCs as well as for other investigators interested in conducting systematic reviews on medical tests. We hope it will be a practical guide both for those who prepare the systematic reviews and those who use them in clinical practice, research development, and in making policy decisions."

Seeking to cross the bridge among overview, theory, and practice, this book incorporates both methodological approaches and their potential application in the domains associated with biomedical informatics.The multi-contributor book is useful for (1) those coming from a domain seeking biomedical informatics approaches for addressing specific needs; and, (2) current biomedical informaticians seeking a foundational background for methods that might be utilized in practical scenarios germane to their ongoing research.A unique characteristic of the text is its balance between foundational coverage of core topics in biomedical informatics with practical "in-the-trenches" scenarios. Contributors represent leading experts from the biomedical informatics field: individuals who have demonstrated effective use of methodology in real-world, high-quality data applications. Contains appendices that function as primers on: (1) Unix; (2) Ruby; (3) Databases; and (4) Web Services.

"Methods of Clinical Epidemiology" serves as a text on methods useful to clinical researchers. It provides a clear introduction to the common research methodology specific to clinical research for both students and researchers. This book sets out to fill the gap left by texts that concentrate on public health epidemiology and focuses on what is not covered well in such texts. The four sections cover methods that have not previously been brought together in one text and serves as a second level textbook of clinical epidemiology methodology. This book will be of use to postgraduate students in clinical epidemiology as well as clinical researchers at the start of their careers.

The acquisition of biomedical research data is continually expanding, both in the number of variables measured in any single experiment and the number of experiments being done. To bring the fruits of all this labor into medical practice, we need to develop techniques for integrating high dimensional assays across experimental studies. In this thesis, I develop and demonstrate several approaches to multiplex meta-analysis, the synthesis multiple of high dimensional studies. I discuss the development of an overall expression map, examining the properties of gene expression dynamics across thousands of studies. I use this analysis of gene expression dynamics to develop methods of integrating highly parallelized gene expression studies to both identify new biomarkers of disease process, and to prioritize genes likely to contribute to disease risk. Finally, I demonstrate a method for clinical genomics, integrating disease linked genetic variants across an entire genome for translation into medical practice.

The retinoblastoma tumor suppressor RB is a central cell cycle regulator. Here we demonstrate that RB can be methylated by SMYD2 at lysine 860, a highly conserved and novel site of modification. This methylation event occurs in vitro and in cells and is regulated during cell cycle progression, cellular differentiation, and in response to DNA damage. Furthermore, we show that RB mono-methylation at lysine 860 provides a direct binding site for the methyl-binding domain of the transcriptional repressor L3MBTL1. This modification may be crucial for regulating the function of RB as a tumor suppressor. Inactivation of RB and activation of the MYC family of oncogenes are frequent events in a large spectrum of human cancers. Here, we sought to also test whether loss of RB function would affect cancer development in a mouse model of c-MYC-induced hepatocellular carcinoma (HCC). We found that RB inactivation has minimal effects on the cell cycle, cell death, and differentiation features of liver tumors driven by increased levels of c-MYC. However, combined loss of RB and activation of c-MYC led to an increase in polyploidy in mature hepatocytes before the development of tumors and a trend for decreased survival after cancer initiation.

Annotation Mercury (Hg) is a global pollutant that knows no environmental boundaries. Even the most stringent control of anthropogenic Hg sources will not eliminate exposure given its ubiquitous presence. Exposure to Hg occurs primarily via the food chain due to MeHgs accumulation in fish. Latest US statistics indicate that 46 States have fish consumption advisories. In addition, Hg is a common pollutant in hazardous waste sites, with an estimated 3-4 million children living within one mile of at least one of the 1,300+ active hazardous waste sites in the US. The effects on intellectual function in children prenatally exposed to MeHg via maternal fish consumption have been the subject of two on-going major, prospective, longitudinal studies in the Seychelles and the Faroe Islands. It is important to recognize that the risk for MeHg exposure is not limited only to islanders with high fish consumption. This bookwill provide state-of-the-art information to the graduate student training in toxicology, risk assessors, researchers and medical providers at large. It is aimed to bring the reader up to date on contemporary issues associated with exposure to methylmercury, from its effects on stem cells and neurons to population studies.

A new paradigm -- Clinical embryology of the abdomen -- Clinical anatomy of the abdomen -- Mechanisms of spread of disease in the abdomen and pelvis -- Intraperitoneal spread of infections and seeded metastases -- The extraperitoneal spaces: normal and pathologic anatomy -- The extraperitoneal pelvic compartments -- Patterns of spread of disease from the liver -- Patterns of spread of disease from the distal esophagus and stomach -- Patterns of spread of disease from the pancreas -- Patterns of spread of disease from the small intestine -- Patterns of spread of disease from the large intestine -- Patterns of spread of renal, upper urothelial, and adrenal pathology -- Patterns of spread of disease of the pelvis and male urogenital organs -- Patterns of spread of gynecologic disease -- Patterns of extraabdominal and extrapelvic spread -- Internal abdominal hernias.

Preparing for the cardiology board examination is an intensely stressful period and traditionally relies on the participant searching through their own references, whether that be the large textbooks, small handbooks and their own notes. Good books are generally too long and time-consuming, while shorter books are either insubstantial in content or rely too much on the views of one author. The key elements for a successful reference for those taking their boards are a balanced proportion of essential content alongside rare but frequently tested topics, the wisdom of experts in the field, a practical questions session at the end of every topic and additional visuals not possible on the two-dimensional page. In the MGH Cardiology Board Review, the Editors have compiled the expertise of over 72 experienced authors from the Mass General in a succinct volume, applying methods thoroughly tested in the Board Review Conference. In addition, two very important sections are included on ECGs and images, contents of which are derived from the board examination answer keys, the very ones that readers are expected to know. Plans on how to best approach the board examination preparation and what additional resources to go to are provided. In short, this book has all the strengths to ensure your success on the boards exam.

B cells internalize antigen bound to membrane immunoglobulin and load antigen-derived peptides onto MHC class II proteins. How these pathways intersect is not well understood. We found that HLA-DM, a catalyst for peptide loading onto MHC class II, regulates immunoglobulin levels in human B cells and co-precipitates with immunoglobulin. In intact cells, HLA-DM and immunoglobulin are found in close proximity, and these complexes are in post-Golgi compartments. In vitro, in the endosomal pH range, the luminal domain of soluble HLA-DM (sDM) directly and specifically interacts with the immunoglobulin Fab domain, and sDM increases the amount of antigen released from immune complexes. These observations support a model in which HLA-DM facilitates the hand-off of antigen from immunoglobulin to MHC class II.

The mhGAP-IG has been developed through an intensive process of evidence review. A WHO Guideline Development Group of international experts conducted systematic reviews to develop evidence-based recommendations. The recommendations were then converted into clearly presented stepwise interventions and then circulated among a wider range of reviewers across the world to include all the diverse contributions. The mhGAP-IG is based on the mhGAP Guidelines on interventions for mental, neurological and substance use disorders (http:// www.who.int/mental_health/mhgap/evidence/en/). Both documents will be reviewed and updated in 5 years. Any revision and update before that will be made to the online version of the document.--(excerpt, p. 1).

This searchable database is a collection of in vivo molecular imaging agents developed for positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound (US), computed tomography (CT), and optical imaging. MICAD, a key component of the "Molecular Libraries and Imaging" program of the NIH Roadmap, is being developed by NCBI, the National Center for Biotechnology Information".

Microarray Image and Data Analysis: Theory and Practice is a compilation of the latest and greatest microarray image and data analysis methods from the multidisciplinary international research community. Delivering a detailed discussion of the biological aspects and applications of microarrays, the book:Describes the key stages of image processing, gridding, segmentation, compression, quantification, and normalizationFeatures cutting-edge approaches to clustering, biclustering, and the reconstruction of regulatory networksCovers different ty.

Microarray technology has made strong progress over the past decade, and there have also been significant changes in application areas, from nucleic acids to proteomics and from research to clinical applications. This book provides a comprehensive overview of microarrays in diagnostics and biomarker development, covering DNA, peptide, protein and tissue arrays. The focus is on entities that are in actual clinical use, or quite close, and on recent developments, such as peptide and aptamer arrays. A further topic is the miniaturisation towards nanoarrays, which is expected to have great potential in clinical applications. Relevant issues of bioinformatics and statistical analysis of array data are discussed in detail, as well as the barriers to the commercialisation of array-based tests and the vexing IP issues involved. Thus, the book should be very useful tor active array users as well as to newcomers seeking to make the best choice between different technologies.

The establishment and wide acceptance of an abundant and diverse human-associated microbial community has been one of the most important shifts in the field of microbiology in the past decade. From a bacterial perspective, the body is a vast landscape whose shifting geography and fluctuating environmental conditions provide a range of distinct residential possibilities. Some habitats, such as the intestinal tract and the oral cavity, have been characterized more extensively than others; within these environs, an understanding of the interplay between microbial ecology and health and disease has begun to emerge. The nasal cavity, a crucial component of both the respiratory system and innate immune system, has yet to benefit from an exploration of similar depth. Recent examination of the nasal microbial habitat has almost exclusively focused on the anterior nares without examining deeper sites within the cavity which are actively involved in nasal mucociliary clearance and exposed to the efflux of various sinuses. The aim of this work was to explore this biogeography by characterizing the microbial communities in a range of spatial sites along the nasal passageway. Additionally, the nasal cavity has long been a source of pathogens, most notably Staphylococcus aureus. Carriage of S. aureus has been demonstrated to be a significant risk factor for acquisition of antibiotic resistant strains of S. aureus and hospital-acquired infections. The second aim of this project was to understand whether underlying community features may be present that were characteristic of S. aureus carriage. 13 healthy subjects (6 persistent and 7 non-persistent carriers) were sampled weekly at 3 different sites (anterior nares, middle meatus, and sphenoethmoidal recess) within the nasal cavity over a 4-week period. The data shows that biogeographical differences were based less upon spatial factors and more on epithelium type. The data also showed that the S. aureus carriage type of the individual contributed the greatest amount of non-S. aureus variation within the communities. Finally, a carriage-classifying model was generated from the data and examined for important predictive features, revealing a potential intra-genus, interspecific competitive interaction in Corynebacterium with implications on S. aureus carriage. These results highlight the complexity present in human microbial communities even within highly spatially constrained microenvironments.

"The field of microbial endocrinology is expressly devoted to understanding the mechanisms by which the microbiota (bacteria within the microbiome) interact with the host ("us"). This interaction is a two-way street and the driving force that governs these interactions are the neuroendocrine products of both the host and the microbiota. Chapters include neuroendocrine hormone-induced changes in gene expression and microbial endocrinology and probiotics. This is the first in a series of books dedicated to understanding how bi-directional communication between host and bacteria represents the cutting edge of translational medical research, and hopefully identifies new ways to understand the mechanisms that determine health and disease"--Publisher's description.

This new volume of Methods in Enzymology continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers microbial metagenomics, metatranscriptomics, and metaproteomics, and includes chapters on such topics as in-solution FISH for single cell genome preparation, preparation of BAC libraries from marine microbial community DNA, and preparation of microbial community cDNA for metatranscriptomic analysis in marine plankton. Continues the legacy of this premier serial with quality chapters authored by leaders in the field.

"The book starts with dissecting mechanisms underlying viral immune evasion via exploiting the host complement system by vaccinia virus, and by modulating the type 1 interferon response by RNA viruses. Yet another chapter looks into how viroporins expressed by different families of viruses causing influenza A virus, SARS, hepatitis C and HIV interact with several cellular pathways. Understanding of these mechanisms can aid the development of novel potential anti-viral targets. The chapter on tuberculosis discusses the emerging importance of the innate immune mechanisms against Mycobacterium tuberculosis infection and latency. This book has a strong focus on fungal pathogenesis and immunity, starting with virulence and host factors that attain great importance in candidiasis and associated escape tricks of seriously opportunistic fungi. Two chapters on Aspergillus fumigatus elaborate on the pathogenic mechanisms: first discussing A. fumigatus-airway epithelium interaction, followed by fungal and host factors that are paramount in the development of allergic and invasive aspergillosis. In the subsequent chapter, there is a general discussion on the innate and adaptive immune responses against primary and opportunistic fungal pathogens"--Publisher's description.

Type of human disease by source of the infectious agent -- A history of zoonoses and sapronoses and research into them -- The infection process in zoonoses and sapronoses -- The epidemic process in zoonoses and sapronoses -- Haematophagous arthropods as vectors of diseases -- Vertebrates as hosts and reservoirs of zoonotic microbial agents -- Systematic survey of zoonoses and sapronoses microbial agents.

One of the most promising new approaches for the prevention of HIV transmission, particularly for developing countries, involves topical, self-administered products known as microbicides. The development of microbicides is a long and complicated process, and this volume provides an overview of all the critical areas, from the selection of appropriate candidate molecules and their formulation, preclinical and clinical testing for safety and efficacy, strategies for product registration and finally, issues associated with product launch, distribution and access. The book will prove valuable to both those working in the field and all others who are interested in learning more about this product class, which has the potential to significantly impact the future of this devastating epidemic.

Problems linked with pathogens in fresh produce, including the associated public health and trade implications, have been reported in a number of countries worldwide. Furthermore, from 1980 to 2004, the global production per annum of fruit and vegetables grew by 94% and they are a critical component of a healthy diet. Reported outbreaks associated with leafy vegetables and herbs have been notable for the wide geographical distribution of the contaminated products, the high numbers of consumers exposed and thus the large number of cases. This meeting addressed the pathways for contamination, survival and persistence of microbiological hazards associated with leafy vegetables and herbs, and the potential management options from primary production through to the consumer.--Publisher's description.

The second edition of Microbiology of Waterborne Diseases describes the diseases associated with water, their causative agents and the ways in which they gain access to water systems. The book is divided into sections covering bacteria, protozoa, and viruses. Other sections detail methods for detecting and identifying waterborne microorganisms, and the ways in which they are removed from water, including chlorine, ozone, and ultraviolet disinfection. The second edition of this handbook has been updated with information on biofilms and antimicrobial resistance. The impact of global warming and climate change phenomena on waterborne illnesses are also discussed. This book serves as an indispensable reference for public health microbiologists, water utility scientists, research water pollution microbiologists environmental health officers, consultants in communicable disease control and microbial water pollution students. Focuses on the microorganisms of most significance to public health, including E. coli, cryptosporidium, and enterovirus. Highlights the basic microbiology, clinical features, survival in the environment, and gives a risk assessment for each pathogen. Contains new material on antimicrobial resistance and biofilms. Covers drinking water and both marine and freshwater recreational bathing waters.

Committee on Microbiomes of the Built Environment: from Research to Application, Board on Life Sciences, Board on Environmental Studies and Toxicology, Board on Infrastructure and the Constructed Environment, Division on Earth and LIfe Studies, Health and Medicine Division, Division on Engineering and Physical Sciences, National Academy of Engineering.

"People's desire to understand the environments in which they live is a natural one. People spend most of their time in spaces and structures designed, built, and managed by humans, and it is estimated that people in developed countries now spend 90 percent of their lives indoors. As people move from homes to workplaces, traveling in cars and on transit systems, microorganisms are continually with and around them. The human-associated microbes that are shed, along with the human behaviors that affect their transport and removal, make significant contributions to the diversity of the indoor microbiome. The characteristics of "healthy" indoor environments cannot yet be defined, nor do microbial, clinical, and building researchers yet understand how to modify features of indoor environments--such as building ventilation systems and the chemistry of building materials--in ways that would have predictable impacts on microbial communities to promote health and prevent disease. The factors that affect the environments within buildings, the ways in which building characteristics influence the composition and function of indoor microbial communities, and the ways in which these microbial communities relate to human health and well-being are extraordinarily complex and can be explored only as a dynamic, interconnected ecosystem by engaging the fields of microbial biology and ecology, chemistry, building science, and human physiology. This report reviews what is known about the intersection of these disciplines, and how new tools may facilitate advances in understanding the ecosystem of built environments, indoor microbiomes, and effects on human health and well-being. It offers a research agenda to generate the information needed so that stakeholders with an interest in understanding the impacts of built environments will be able to make more informed decisions"--Publisher's description.

This book presents a new method for analyzing the structure and function of the biological branching systems of fractal trees, with a focus on microcirculation. Branching systems in humans (vascular and bronchial trees) and those in the natural world (plants, trees, and rivers) are characterized by a fractal nature. To date, fractal studies have tended to concentrate on fractal dimensions, which quantify the complexity of objects, but the applications for practical use have remained largely unexplored. This book breaks new ground with topics that include the human retinal microcirculatory network, oxygen consumption by vascular walls, the Fh raeus-Lindqvist effect, the bifurcation exponent, and the asymmetrical microvascular network. Readers are provided with simple formulas to express functions and a simulation graph with in vivo data. The book also discusses the mechanisms regulating blood flow and pressure and how they are related to pathological changes in the human body. Researchers and clinicians alike will find valuable new insights in these pioneering studies.

In vivo target site concentrations are probably the most important determinant of drug effects. Traditionally, linking drug concentrations to drug effects has been accomplished by modelling blood-derived data, mostly because a direct quantification of tissue concentrations has been beyond technical reach. Today, a direct measurement of target site concentrations is possible by employing microdialysis or complementary approaches such as imaging technologies. Microdialysis, initially conceived in the 1970s, has become a standard tool in drug development. This comprehensive overview of current microdialysis technology covers general and disease-specific aspects of microdialysis by international experts in the field. It provides useful information for colleagues in academia and industry who are interested PK-PD aspects of drug development.

Nanoscience and nanotechnology have been applied in recent years to cancer research, with the goal of bringing about a revolutionary change in the ways in which cancer is diagnosed and treated. Magnetic nanotechnologies, in particular, have shown significant potential in several areas, such as imaging, therapeutics, early detection, and point-of-care therapy monitoring. Most applications of magnetic nanotechnology in cancer research involve the use of nanoscale magnetic carriers. Depending on the properties of the particular carrier and the manner in which they are employed, magnetic carriers can act as MRI contrast enhancing agents, drug delivery vehicles, bio-labels for detection with magnetic biosensors, or selection agents in immunomagnetic separation platforms. The small sizes (10-100 nm), functional surface chemistries, and controllable magnetic responses of nanoscale magnetic carriers allows for interaction with and control of biological entities in both novel and powerful ways. The focus of this thesis is on a specific application of magnetic carriers -- magnetic separation of biomolecules and rare cells. After an introduction and an overview of magnetic separation principles are given in Chapters 1 and 2, Chapters 3-6 discuss the design, fabrication, and use of a novel magnetic separation device, the magnetic sifter. The magnetic sifter is a microfabricated, 7 x 7 mm planar die containing a dense array of pores (~200-5000/mm^2) in a magnetically soft membrane. When magnetized by an external field, the sifter pores generate large magnetic field gradients (~10^6 T/m) near the pore edges, which can capture nanoscale magnetic carriers with high efficiency and throughput. The gradients can be turned off by removing the external field, and the magnetic carriers can be released. The magnetic sifter is a microfluidic device, in the sense that it contains microfabricated, micron-scale pores which generate large field gradients. It is also a macrofluidic device, in that high volume throughput is achieved by parallel flow through the dense array of pores. Magnetic modeling of the magnetic sifter and a method for its fabrication are presented in Chapters 3 and 4. When paired with magnetic carriers functionalized with recognition moieties, the magnetic sifter can be used in both protein and cell enrichment schemes. The focus of Chapter 5 is on using the magnetic sifter to capture individual magnetic nanoparticles. The intended application is for enrichment of cancer protein markers prior to detection with a magnetic spin-valve biosensor. High capture efficiencies (80-100%) of magnetic nanoparticles have been achieved for a single pass through the magnetic sifter. Magnetic nanoparticles can also be released from the magnetic sifter with nearly 100% efficiency. The focus of Chapter 6 is the use of the magnetic sifter for rare cell enrichment, for applications in enumeration and enrichment of circulating tumor cells. It is shown that the magnetic sifter can capture tumor cells from whole blood with high efficiency and throughput (~60% at 5 ml/hr). Furthermore, with its planar structure and presentation of captured cells, the magnetic sifter doubles as a cell imaging platform, allowing for identification and quantification with optical microscopy. In addition to its high capture efficiency and gentle release of captured cells, the small size and scalable fabrication of the magnetic sifter are attractive for applications in point-of-care cancer diagnostics for early detection and monitoring of metastatic disease. In Chapter 7, a method for high-throughput fabrication of novel magnetic carriers, synthetic antiferromagnetic (SAF) nanoparticles is presented. The method has enabled production of large quantities of SAF nanoparticles, which have desirable properties for applications in magnetic separation. The capture and release behavior of SAF nanoparticles with the magnetic sifter has been demonstrated. High capture efficiencies are achieved at flow rates 10-20x higher than what was previously possible with commercially available magnetic carriers. Both the magnetic sifter and physically fabricated SAF nanoparticles offer unique advantages over traditional technologies. They are each, in their own right, promising new technologies for applications in cancer detection and therapy monitoring.

Phase transitions are ubiquitous in nature. Fundamental study of phase transition phenomena is a cornerstone of condensed matter physics, and theoretical results in this area guide technology development in material science. Phase transitions also play an important role in biology. Biological macromolecule phase transitions occur in many biological processes, for example the gel-liquid transition in lipid bilayers and amyloid formation in protein aggregation disease. From a technological standpoint, the ability to crystallize proteins has enabled one of the most important advances in biology of the last century: protein structure determination with X-ray crystallography. However, biological macromolecule phase transitions often display stark phenomenological differences from their inorganic analogs. This owes to the sheer size and complexity of proteins and nucleic acid complexes. Macromolecular phase transition theory is rich in subtleties, anecdotal & counter-intuitive results, and often diverges from predictions of classical theory. In addition to developing theory, fundamental study in this area is also critical for improvements in high-throughput crystallography efforts and in understanding mechanisms of devastating neurodegenerative diseases. This thesis approaches the study of macromolecule phase transitions through the development of new measurement technology. In this work, spectroscopic and imaging techniques are combined with microfluidic systems to provide insight into three areas of macromolecule phase transitions. First, dynamic light scattering and microscopy are integrated onto a microfluidic platform to study and optimize protein crystallization. Additionally dynamic light scattering is combined with fluorescence spectroscopy to investigate amyloid fibril aggregation. Finally, a new technology is presented that demonstrates high-throughput mapping of macromolecule structure by integrating single-molecule fluorescence resonance energy transfer spectroscopy with a microfluidic mixing platform. This lab-on-a-chip platform enables examination of conformational transitions in nucleic acids in response to changes in the chemical and molecular environment in order to create a conformational "phase diagram". In addition to presenting new insight into the mechanism of protein crystallization and protein aggregation, this thesis introduces new technologies for studying biological macromolecule phase transitions.

Protein--DNA interactions are responsible for numerous critical cellular events: for example, gene expression and silencing are mediated by transcription factor protein binding and histone protein modifications, and DNA replication and repair rely on site specific protein binding. Chromatin immunoprecipitation (ChIP) is the only molecular assay that directly determines, in a living cell, the binding association between a protein of interest and specific genomic loci. It is an indispensible tool in the biologists' toolbox, but the many limitations of this technique prevent broad adoption of ChIP in biological studies. The typical ChIP assay can take up to one week to complete, and the process is technically tricky, yet tedious. ChIP assay yields are also low, thus requiring on the order of millions to billions of cells as starting material, which makes the assay unfeasible for studies on rare or precious samples. Cancer stem cells (CSCs), for instance, are obtained from primary tumors, and FACS sorting of the dissociated tumor cells rarely yields more than ~100,000 CSCs per tumor. This thesis describes the microfluidics-based strategies for performing ChIP. The first design for a microfluidic ChIP design utilizes the automation and scalability aspects of microfluidics to reduce both total and hands-on assay time, and improve throughput. It can take chromatin prepared using any existing ChIP protocol as input, and generate ChIP-qPCR results in just 1 day. The device is shown to be comparable to existing ChIP protocols, and can detect cellular epigenetic changes induced by external cytokine stimulants. It was used to investigate transcription factor binding dynamics in an aging-related pathway, and was able to link transcription factor binding to local changes in histone modifications. The second design of the microfluidic ChIP platform focuses on addressing the cell number requirements of ChIP. In addition to reducing assay time through automation, this design incorporates microfluidic designs that allow whole fixed cells as input, and enables automated ChIP from as few as 2,000 cells. Finally, using this high-sensitivity ChIP device in conjunction with next-generation sequencing technology, a protocol for determining genome-wide epigenetic landscapes from as few as 2,000 cells is developed, with the ultimate goal of performing protein-DNA association studies on CSCs.

"Micropatterning refers generally to techniques which provide an experimental control over the chemical, physical, or geometrical properties of materials at the micron or submicron scale, and are thus used to produce spatial patterns of these properties. These techniques, which were often originally designed for application in microelectronics, have spread over most areas of science, including biology. They have proved particularly useful for cell biology, bridging the gap between the Petri-dish and complex 3D assays and tissues."--Preface.

"This book reflects the current state of knowledge about the role of microRNAs in the formation and progression of solid tumours. The main focus lies on computational methods and their applications in combination with cutting edge experimental techniques that are used to approach all aspects of microRNA regulation in cancer. The use of high-throughput quantitative techniques makes an integrative experimental and computational approach necessary. This book will be a resource for researchers starting out with microRNA research, but is also intended for the experienced researcher who wants to incorporate concepts and tools from systems biology and bioinformatics into his work. Bioinformaticians and modellers are provided with a general perspective on microRNA biology, and the state-of-the-art in computational microRNA biology." --Publisher's description.

Much has been learned about the molecular and cellular components critical for the control of immune responses and tolerance. It remains a challenge, however, to control the immune response and tolerance at the system level without causing significant toxicity to normal tissues. Recent studies suggest that microRNAs (miRNAs), an abundant class of ~22 nucleotides regulatory RNAs, play important roles in immune cells. In this thesis, I examined the function of miR-181 genes in regulating T cell selection, development, and immune tolerance. We show that genetic ablation of mir-181a-1/b-1 ---- a T cell sensitivity tuner ---- in double-positive (DP) thymocytes dampens TCR and Erk signaling and affects positive selection. Moreover, dampening TCR signaling as the result of mir-181a-1/b-1 deletion potentiates the reactivity of self-specific T cells without significantly affecting the pool sizes of naive T cells recognizing specific self-antigens. Finally, loss of mir-181a-1/b-1 in peripheral T cells reduces their basal TCR signaling and their ability to migrate from lymph nodes to the pathogenic sites during autoimmune perturbations. Interestingly, loss of mir-181a-1/b-1 results in quantitative defects in various T and B lymphocyte populations, but does not cause major structural damage to the immune system or spontaneous autoimmunity. Our findings illustrate that mir-181a-1/b-1 controls tolerance through opposing activities in selection and peripheral T cell function. Thus, despite the subtle effects of miRNAs on gene expression, miRNAs have the potential to influence the outcomes of normal and pathogenic immune responses by controlling the quantitative and dynamic aspects of immune responses.

The field of microRNA biology is really emerging in the last couple of years. Several investigators highlighted the importance of miRNAs in cancer. Although there is so much literature on microRNAs exist, a comprehensive book is still not available. Thus this book will be a great use to the scientists in the field of cancer biology. In addition, this book will be a good source of information for undergraduate, graduate students who want to develop their research careers in cancer biology.

Mammalian neurogenesis - an elagant process of producing extraodinarily diversified neuronal propulations - has been largely studied in the context of evoluationarily conserved signalling pathways and neurogenic transcription factors. Yet little is known about the roles of chromatin remodellers and regulatory RNAs, such as microRNAs, in the formation of neurons. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes during murine nervous development, a process important for neuronal differentiation and function. Here I set out to directly test the neurogenic activity of these microRNAs in human non-neuronal cells. Together with Andrew Yoo, I showed that ectopic expression of miR-9/9* and miR-124 (miR-9/9*-124) in human dermal fibroblasts induces their conversion into neurons (chapter 2). Addition of neurogenic transcription factors such as NEUROD2, ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 appeared ineffective. As a step closer to cell replacement therapy, I next showed that these microRNAs could directly convert human astrocytes into neurons, of which the subtype identity can be further biased by specfic neurogenic factors (chapeter 3). Collectively, these studies indicate that the genetic circuitry involving miR-9/9*-124 and BAF chromatin remodelling complex can have an instructive role in neuronal fate determination, and may form a neuronal ground state that can be further specified by different transciption factors and/or signalling pathways.

The book serves as a comprehensive resource for scientists and clinicians studying the role of non-coding RNAs in inflammation (viral infections, wound inflammation), human inflammatory diseases (i.e. rheumatoid arthritis, Crohnℓ́ℓs disease, diabetes), and innate immunity. It provides a universal reference work comprising both basic and specialized information. Given that ncRNAs represent new therapeutic targets, this volume will also be of interest to industrial biomedical researchers and those involved in drug development.

"MicroRNAs are small, non-coding RNA molecules that interact with target mRNAs to modulate their translation. They are now recognized as widespread and critical regulators of gene expression in the cell. This book is aimed at both industry- and academic-based researchers in the Biopharmaceutical production space who wish to learn more about these fascinating molecules..."--Page [4] of cover.

Microsatellites or simple sequence repeats (SSRs) have become the markers of choice for a variety of molecular studies because of their versatility, operational flexibility, and lower cost than other marker systems. Microsatellites: Methods and Protocols brings together experts in the field to cover this significant area of research. Broken in to four convenient parts, this volume delves into classical and modern methods for the discovery and development of microsatellite markers, descriptions of amplification and visualization of SSRs, automated capillary sequencers that are widely used for fragment analysis, as well as a variety of methods for the analysis of data obtained by the use of microsatellites. Written for the highly successful Methods in Molecular Biology series, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and invaluable, Microsatellites: Methods and Protocols aims at researchers that need detailed protocols for incorporating microsatellite markers into their projects and expert scientists looking to expand their knowledge of SSRs discovery, use, and analysis.

"In the past two decades, significant advances in magnetic resonance microscopy (MRM) have been made possible by a combination of higher magnetic fields and more robust data acquisition technologies. This technical progress has enabled a shift in MRM applications from basic anatomical investigations to dynamic and functional studies, boosting the use of MRM in biological and life sciences. This book provides a simple introduction to MRM emphasizing practical aspects relevant to high magnetic fields. It focuses on biological applications and presents a number of selected examples of neuroscience applications. The text is mainly intended for those who are beginning research in the field of MRM or are planning to incorporate high-resolution MRI in their neuroscience studies."--Provided by publisher.

This book provides the anatomy of the posterior fossa, together with the main associated surgical techniques, which are detailed in numerous photographs and step-by-step color illustrations. The text presents approaches and surgical techniques such as the trans-cerebellomedullary fissure approach and its variation to the fourth ventricle, as well as the cerebellomedullary cistern, infratentorial lateral supracerebellar approach to the fifth cranial nerve in the upper cerebellopontine angle, infrafloccular approach to the root exit zone of the seventh cranial nerve, transcondylar fossa approach through the lateral part of the foramen magnum, and the stitched sling retraction technique utilized during microvascular decompression procedures for trigeminal neuralgia and hemifacial spasm. It also describes in detail the bridging veins of the posterior fossa, especially the petrosal vein, and bridging veins to the tentorial sinuses, which can block approaches to the affected area. The original Japanese version of this work was published 8 years ago, and has established itself as a trusted guide, especially among young neurosurgeons who need to study various surgical approaches and techniques. In the course of being translated into English, some sections have been revised and new information has been added. The author hopes that the book will help neurosurgeons around the world perform safer operations with confidence.

With each heart contraction, blood rushes throughout the expansive circulatory system providing oxygen and other nutrients to the body. Cardiomyocytes are the contractile units responsible for these contractions. In the event of ischemia, the heart reduces its contractile output and loses a significant number of cardiomyocytes. In the ischemic region of the heart, the tissue remodels and the mechanical properties differ significantly from healthy tissue. Due to the limited regeneration capabilities of the heart, recent focus has been on understanding how the reintegration of pluripotent-derived cardiomyocytes can help restore contractile function. These pluripotent-derived cardiomyocytes will need to survive in mechanically active environments and contribute to the contractile output of the heart. However, even before these cardiomyocytes can be used, we need to develop an understanding for how primary immature cardiomyocytes should respond to mechanical forces in vitro. This work explores cardiomyocyte contractile ability in the presence of mechanical forces. For this work, we investigate neonatal murine cardiomyocytes. We begin by developing a protein patterning technique suitable for polyacrylamide. With this technique, we achieve repeatable arrays of neonatal cardiomyocytes and control their shape and size. We found this technique improves sarcomere distribution, making them look more mature and like adult cardiomyocytes. Using micro-tools, we then investigate cardiomyocyte contractility in the presence of mechanical forces. These findings suggest that the Frank-Starling law that governs the heart is also applicable to neonatal cardiomyocytes. Later in this work, we introduce the MEMS tool developed to better understand cardiomyocyte contractile forces. We describe the design goals and fabrication process of the micro-device. In addition, we present the calibration and testing results, and demonstrate that this device provides a reliable and alternative way to calibrate substrates used to study contractile forces. In the closing section of this work, we introduce ideas for future studies building on this work, and the work of others.

"Remarkable progress in the development of new concepts and techniques used in reconstructive surgery of microtia/atresia of the external auditory canal (EAC) has been made since the beginning of the 21st century. Helical computed tomography has made a three-dimensional reconstruction of the soft tissue of the temporal bone surface and the cranium possible, and has laid the groundwork for a collaboration between plastic surgeons and otologists. This book presents the latest findings on reconstructive surgery performed jointly by plastic surgeons and otologists. Based on this concept, information on diagnosis, surgical procedures, outcomes, long-term results and psychology is discussed. Collaborative surgery offers advantages not only in terms of a better reconstruction of morphology and function, but also in terms of the lower number of surgical procedures required which reduces the psychological pressure and economic burden on patients."--Publisher's website.

Stable Tubule Only Polypeptides or STOP proteins are a class of microtubule-associated proteins that are unique in that they have been shown to protect microtubules from depolymerization under destabilizing conditions. To date, MAP6 and the related protein MAP6 domain containing 1 (MAP6D1) are the only known mammalian STOP related proteins. However, through a recent screen identifying genes upregulated during ciliogenesis in multiciliated tracheal cells, we have identified two new uncharacterized mammalian MAP6 related proteins, FAM154A and FAM154B. Though MAP6 has not been previously shown to localize to the primary cilium and centrosome, we sought to assess the ability of these new proteins to stabilize microtubules and their potential function at the cilium and centrosome. Proteins related to FAM154A and FAM154B are found in all vertebrates and most organisms containing cilia and centrosomes including drosophila and chlamydomonas. A C. elegans homolog of the protein has been localized to neuronal cilia and mammalian FAM154B, much like MAP6 is expressed in mammalian cortical neurons. Overexpressed FAM154A and FAM154B localize to the centrosome and the primary cilium and overexpressed FAM154A protein and deletion variants stabilize microtubules against cold treatment in RPE1 cells. Endogenous FAM154A and FAM154B localize to centrosomal structures and cilia respectively in multi-ciliated cells. Similar to MAP6, FAM154A and Fam154B also contain repeated motifs in their amino acid sequences, however their protein level similarity to MAP6 is very limited. We have shown that FAM154A is a bona-fide microtubule associated protein via biochemical assays and can interact directly with microtubules and with calcium calmodulin which may modulate its microtubule binding affinity, similar to MAP6. Ongoing work to resolve the molecular structure of these MAP6 related proteins will illuminate their exact mechanism of microtubule stabilization.

Microwave ablation is a simple, affordable, and highly precise technique. After its successful application in treating liver tumors, it is now widely used to combat renal tumors, adrenal tumors, thyroid nodes, uterine fibroids and other solid tumors. This book presents 40 successful cases of treating these diseases. A series of picture before treatment, after treatment and from different angles is provided for each kind of tumor treatment. In each chapter, step by step operative techniques and illustrations are included. This book also examines CT, NMR and ultrasonography to evaluate the effect of microwave ablation. Editor Ping Liang, is the Director and Professor at Dept. of Interventional Ultrasound, General Hospital of PLA, Beijing, China. Editor Xiaoling Yu is Professor and Chief physician, Editor Jie Yu is Associate Chief physician at the same department.

The middle ear plays a vital role in the sense and sensitivity of hearing. Of the various characteristics that distinguish mammals from other vertebrates, several pertain specifically to the middle-ear system, such as the presence of three middle-ear bones and the four-layer composite structure of the tympanic membrane. The Middle Ear attempts to elucidate the role this system plays in sound transmission, as viewed from both scientific and clinical perspectives.

Business vows : what is a proposal and why it is necessary -- Five steps toward great leaps : how to prepare yourself and the client -- Avoiding gatekeepers, intermediaries, and goblins : accepting rejection and rejecting acceptance -- The architecture of successful proposals : the million dollar consulting proposal structure -- One dozen golden rules for presenting proposals : steak and sizzle are hard to beat -- Why bad things happen to good people who wait : moving mountains -- First, let's kill all the lawyers : Shakespeare really meant that we needed them -- The dreaded RFP (request for proposals) : why fill out the truly boring in triplicate? -- Retainers are to projects as Montrachet is to Thunderbird : the wonder of access to your smarts -- In the unlikely event you need oxygen : we don't anticipate a crash, but there are some things you ought to know.

Using a clinically relevant, systems-based approach, this medical textbook accessibly explains the microbiology of the agents that cause diseases and the diseases that affect individual organ systems. With lavish illustrations and straightforward, accessible explanations, Richard Goering makes this complex subject simple to understand and remember. 150 multiple choice review questions. "Pathogen Parade" and many other features to enhance learning and retention. Enhance your learning and absorb complex information in an interactive, dynamic way. Deepen your understanding of epidemiology and the important role it plays in providing evidence-based identification of key risk factors for disease and targets for preventive medicine. A completely re-written chapter on this topic keeps abreast of the very latest findings.

In the culminating volume of her nationalism trilogy, Greenfeld argues that we have overlooked the connection between egalitarian society and mental illness. Modern nationalism rests on principles of popular sovereignty, equality, and secularism. Citizens of the twenty-first century enjoy unprecedented freedom to become the authors of their personal destinies. Empowering as this is, it also places them under enormous psychic strain. They must constantly appraise their identities, manage their desires, and calibrate their place within society. For vulnerable individuals, this pressure is too much. Training her analytic eye on extensive case histories in manic depression and schizophrenia, Greenfeld contends that these illnesses are dysfunctions of selfhood caused by society's overburdening demands for self-realization. In her rigorous diagnosis, madness is a culturally constituted malady.

Welcome -- Mindfulness -- Week 1: Introduction to Mindfulness -- Week 2: The five elements of mindfulness -- Week 3: Integrating mindfulness into every day life -- Week 4: Mindfulness as a way of life -- Week 5: Mindfulness as a home base for therapists -- Week 6: Mindfulness of the body -- Week 7: Integrating mindfulness into therapeutic practice -- Week 8: Review and next steps -- Week 9: Your Oasis -- Extending your practice -- Exercises in everyday personal and professional lives -- Mindfulness exercises for the helping role -- Mindful moments with your clients -- Short Manual for running a group based on the presented material.

Norms are prescribed conducts applied by the majority of people. Getting across cultures and centuries, norms evolved to rule all human relationships, from the most formal to the most intimate. Impinging on any sphere of life, from religious to political, norms affect social, moral, and even aesthetical behaviours. They are enforced through centralized sanctions or distributed control, and originate through deliberate acts of issuing or from spontaneous interaction in informal settings. Despite ubiquity and universality, norms are still awaiting for a general comprehensive theory, simultaneously doing justice to three intuitions: that, under variable contents, norms correspond to a common notion; that, once brought about, norms feedback on their producers, affecting their conducts; and finally that before and in order to drive the behaviours of individuals, norms must affect their beliefs and goals: people must detect and accept norms before converting them into observable behaviours. This volume presents an unprecedented attempt to account for all the three intuitions at once, providing a systematic view of norms. Based on a unitary and operational notion of norms, as behaviours spreading thanks to and to the extent that the corresponding prescriptions spread as well, a cognitive architecture, EMIL-A, which is the main output of a research project on norm emergence, is described. EMIL-A is a BDI-like platform for simulation, endowed with modules for detecting, reasoning and deciding upon norms. Next, the EMIL-A platform is applied to generate norms in different simulated scenarios (from a multi-setting world to a virtual Wikipedia), through a complex bidirectional dynamics, i.e., the bottom-up emergence of norms thanks to a gradual, top-down process, denoted as immergence. As simulations results show, norms emerge while immerging in agents' minds, thanks to their detecting, reasoning, and deciding whether to respect them or not.

In recent years, mini-invasive surgery has become increasingly important for reducing the risk of infection and minimizing blood loss and volume of implants. Hip surgery requires small incisions, which make the use of the appropriate equipment and an extensive knowledge of the anatomy of the region essential. Mini-invasive surgery requires the surgeon to consider the indications for surgery for each patient he treats and to know the exact loco-regional anatomy for that patient. Methods must be very precise and warrant visual explanations to help teach young surgeons.

Fluorescence microscopy has emerged as a workhorse of modern biology and medicine. Fluorescence microscopes are indispensable as tools for basic research in the biological sciences, enable platforms for drug discovery in the biotechnology and pharmaceutical industries, and are increasingly aiding in several clinical diagnostic applications. However, state-of-the-art fluorescence microscopes remain bulky and expensive benchtop instruments with an architecture that impedes usage in certain applications and a cost that precludes adoption in large numbers. For example existing benchtop fluorescence microscopes are not amenable for in vivo imaging in animals, with the mouse being a common animal subject, especially during awake, active behavior. For the field of neuroscience in particular, such an experimental capability permits correlating causal cellular processes with animal behavior -- a longstanding goal. Inspired by this need, we have designed a miniature fluorescence microscope that can be borne by a mouse during active behavior. We have fabricated several such microscopes, each less than 2 g in mass, perhaps heralding a transformation in fluorescence microscopy from today's bulky and expensive benchtop paradigm towards miniature and mass-producible devices. Our fabricated microscopes achieve 2.5 μm spatial resolution imaging fields-of-view up to 800 μm x 600 μm at 36 Hz, suitable for cellular-level imaging at high temporal resolution. To facilitate design of our microscopes, we have adopted a modeling-based microscope design methodology, akin to that used in the design of integrated circuits, and have developed a set of tools to model the microscope as an integrated device from the specimen to final digital image. We have experimentally validated fabricated microscopes for in vivo brain imaging in freely behaving mice, specifically using them for: 1) Imaging cerebellar vasculature and hemodynamics during activity; and 2) Imaging cerebellar Purkinje cell Calcium dynamics, analyzing spiking activity of populations of neurons with single neuron specificity during different motor behaviors. We also show how several of these microscopes imaging in parallel can enable new high-throughput imaging solutions with the potential to achieve broad impact, specifically demonstrating high-throughput image-based assays for: 1) Mutant phenotype screening in genetic model species such as the zebrafish; and 2) Multiple well plate cell analyses. Finally, we use a Bayesian iterative image restoration algorithm to enhance acquired microscope images, and show how spatial resolution can be further scaled into the sub-micron regime by leveraging advances in digital image sensing technology in conjunction with our post-acquisition image restoration algorithm.

This contributed volume regenerates the significance of and respect for natural phenomenon in the background of the risks and complications seen in ART such as ovarian hyperstimulation and multiple pregnancies. Balancing the clinical practice between the beneficial natural physiology and the prolific use of stimulation drugs for ART may help eliminate risks that may prove clinically, financially and psychologically expensive. It underscores the fact that 'greater' is not always synonymous with 'better' with regard to the oocyte yield. While highlighting the risks involved with the use of high-dose gonadotropins, the book presents a stratification of patients who might benefit from the 'soft' minimal and natural cycle IVF stimulation protocols that may be used. Additionally, clinicians can understand the significance of cryopreservation technology, now a useful adjunct to minimal stimulation protocols, with its manifold future advantages. Written by an international team of experts, this handbook emphasizes how minimal stimulation and natural cycle IVF can lead to a milder, safer and more effective approach to ART. .

"Minimally Invasive and Robotic Thyroid and Parathyroid Surgery is the first textbook which includes a comprehensive review of both minimally invasive and robotic thyroid and parathyroid techniques. Over the last several years there has been a rapid expansion in the number of different surgical approaches available to patients undergoing thyroid and parathyroid surgery. This book consolidates these in one source and focuses on both the philosophy and techniques of these procedures. For thyroid surgery, the text covers the full range of minimally invasive procedures and several of the most widely adopted remote access techniques. Several related procedures are also discussed, including minimally invasive approaches to central and lateral neck dissection. For parathyroid surgery, several minimally invasive techniques are covered, including radioguided surgery. Written by experts in the field of thyroid and parathyroid surgery, Minimally Invasive and Robotic Thyroid and Parathyroid Surgery serves as a critical resource for both experienced and less experience surgeons, fellows, residents, and students interested in understanding the breadth of this field or learning the specific steps of a particular technique."--Publisher's website.

This book explains the concept of metabolic surgery and provides step-by-step descriptions of all the principal minimally invasive surgical techniques employed to treat morbid obesity. The approach adopted is very practical. For each procedure, indications, technical aspects, clinical management, and outcomes are described, and helpful tips and tricks, highlighted. Guidance is provided on the management of emergencies and potential complications, as well as on general postoperative management and long-term follow-up. The coverage also includes new frontiers of robotic and endoscopic surgery. While the focus is on surgical techniques, emphasis is placed on the need for a multidisciplinary approach, with explanation of the role of the multidisciplinary team and the bariatric center. In addition, important information is presented on the definition of morbid and severe obesity, incidence/prevalence, pathophysiology, and obesity-related comorbidities. The authors are internationally acknowledged experts who present best practice know-how in the field and draw on the most recent research literature.

The second edition of Minimally Invasive Bariatric Surgery provides a comprehensive, state-of-the art review of this field, and it serves as a valuable resource for clinicians, surgeons and researchers with an interest in minimally invasive bariatric surgery. Additionally, the second edition includes new features that will benefit the resident, fellow, or bariatric surgeon new to the field. Specifically, each evidence-based chapter (i.e. outcomes, complications, epidemiology, etc) concludes with three or four exam questions that emphasize the salient points of the chapter and provide fellowship programs a valuable training tool and resource for their academic curriculum. These questions are either single-answer multiple choice or true/false format and the correct response with a brief explanation follows. As more emphasis is placed on completing a comprehensive curriculum and obtaining certification for bariatric training, this aspect of the book is unique and provides added value to the text. The new edition also incorporates many new or updated medical illustrations to enhance the technique chapters and provide more uniformity for the artwork throughout the book. Each of the major procedures include surgical technique, outcomes, and management of complications in separate chapters to provide an easy reference for the busy clinician preparing for a case or presentation. Another unique feature of the text is a link to video files hosted online for the relevant chapters. This video library will be of great value to the user. As the number of fellowships in laparoscopic bariatric surgery continues to increase, this updated text will provide a valuable resource for general and bariatric surgeons, laparoscopic surgeons, fellows, residents, medical students, obesity researchers, and industry representatives involved in this field. Minimally Invasive Bariatric Surgery is a valuable resource for Medical students, surgical oncology fellows, general surgeons, and educators.

As minimal access approaches to cancer diagnosis, staging, and therapy become more widely used, it is vital for general surgeons, along with laparoscopists, surgical oncologists and medical oncologists, to stay up to date. The editors, a team consisting of a renowned surgical oncologist and a laparoscopic specialist, aim to provide a resource for the practicing general surgeon using basic minimally invasive techniques. The book discusses diagnosis including biopsy with microinstrumentation, staging, and palliative and curative resection. Specific tumor sites are addressed, including esophagus, stomach, spleen, small bowel, pancreato-biliary, hepatic resection, and colo-rectal resection. Minimally invasive approaches to the thoracic and retroperitoneal areas are included. The book provides a thorough overview of basic cancer biology, instrumentation, and ultrasound. Additionally, Greene and Heniford explore controversial issues such as port-site recurrence and the effect of pneumoperitoneum on the spread of cancer cells in the abdomen. Many photographs and line drawings, including 16 in full color, illustrate the principles discussed in the text. A must-have for every practicing general surgeon, laparoscopic fellow, and general surgery resident.

Minimally Invasive Forefoot Surgery in Clinical Practice describes a number of the better established and accepted minimally invasive surgical correction techniques for forefoot problems, and is aimed at junior and general orthopedic surgeons who require a useful easy reference for these procedures.The concise written text is complemented by a generous assortment of useful photos, diagrams, and imaging studies.

This book provides detailed, comprehensive and illustrative content to the surgical community in the areas of foregut oncologic surgery. The text contains an in-depth review of all surgical aspects of oncologic diseases involving the stomach and esophagus. The main focus is on the minimally invasive techniques including potential complications and their management. The text also includes an online link to the videos for all minimally invasive foregut surgical procedures, including animation content which provide a more comprehensive learning experience. Minimally Invasive Foregut Surgery for Malignancy: Principles and Practice is structured in a way that makes it useful at every level of training and will be of great utility to practicing surgeons, fellows in surgical subspecialty training and surgical residents.

Daniel H. Kim, MD, FACS, Kyung Hoon Kim, MD, and Yong Chul Kim, MD, helps you apply methods of spinal pain relief that involve less risk and shorter recovery times. Focusing on the broad appeal of this goal for you and your patients, this volume will help surgeons and specialists in various areas of pain management provide less invasive alternatives and faster recovery procedures for those suffering with spinal injuries. Step-by-step techniques are well-illustrated in the book and demonstrated extensively on DVD. Reduce the risk associated with invasive spinal procedures by considering new perspectives on pain management techniques that can be used by specialists from various disciplines. Address the growing need for less invasive surgeries with shorter recovery times among a large and aging population with musculoskeletal problems. You and your patients both want less invasive, less risky options for faster recovery & better outcomes.

Contemporary spinal surgeons, whether orthopedic or neurosurgeons, are increasingly recognizing minimally invasive spine surgery (MISS) as a valuable option for managing advanced degenerative diseases. MISS techniques minimize blood loss and surgical site pain, while speeding recovery. Thus, the combination of MISS with adult spinal deformity was a natural choice. Currently, the techniques, technologies, and education of surgeons have finally reached a point where MISS deformity surgeries are becoming commonplace. Nevertheless, the field is young enough (and still evolving) that no comprehensive texts have addressed the unique challenges it poses for surgeons. This book fills that gap.

Over the past decade, minimally invasive techniques have developed rapidly and are widely applied in the management of spine disorders. With the development of enabling technologies, including specifically designed spinal retractor systems, intra-operative imaging and navigation technologies, and real-time neural monitoring, minimally invasive spine surgery (MISS) techniques are safe, effective and reproducible. Indeed, studies have confirmed the clinical and economic advantages of these procedures. Minimally Invasive Spine Surgery includes detailed discussions of enabling technologies, surgical techniques (including posterior decompression and fusion), approaches to specific diseases and conditions, as well as strategies to manage the unique risks and complications of MISS. Generously illustrated, this will be an essential reference for orthopedic surgeons, neurosurgeons and all health care professionals who treat the spine.

Minimally Invasive Surgery for Achilles Tendon Disorders in Clinical Practice is a collection of procedures presented by experts and pioneers in foot and ankle surgery who share an interest in developing less invasive methods of treating disorders of the foot and ankle. The rate of complications of traditional surgery is extremely high: in the management of tendinopathy, traditional techniques result in 10% of patients experiencing a complication related to skin healing. It is therefore not surprising that less invasive techniques have been advocated.This book will serve as an excellent pocket reference when repairing disorders of the Achilles and aimed general orthopedic surgeons and specialist who require a useful easy reference for these procedures.

The treatment of liver diseases comprises a significant component of the practice of any general surgeon, whether working in an academic, a general, or a community hospital. With the rapid expansion in knowledge and technology, the liver has also been approached laparoscopically in specialized centers, with well-recognized advantages for patients. This book aims to communicate the large body of experience that has now been accumulated in minimally invasive liver surgery, with comprehensive and up-to-date information on the newest techniques. After a concise description of the main tools and technology necessary to carry out safe laparoscopic and/or robot-assisted liver surgery, individual operative techniques are explained and illustrated. Each chapter includes introductory information, a summary of indications and contraindications, and a detailed description of surgical procedure, including potential complications of both the surgery and the postoperative care. Special efforts have been taken to ensure that the illustrations are accurate and informative. The text is supplemented by a DVD of different procedures as performed by leading European liver surgeons.

Minimally invasive procedures are increasingly utilized and are replacing open surgery to reduce scarring and pain, enhance patient recovery, and minimize cost. This guide provides step-by-step guidance, expert instruction, and detailed illustration of the most recent minimally invasive orthopedic spine procedures. With a variety of chapters covering critical developments in the field including the utilization of biologic materials, image-guided surgery, and bone fusion, this guide delves into discussions of indications, methods for preoperative planning, complication avoidance strategies.

The past 20 years have witnessed an extraordinarily rapid adoption of minimally invasive surgical techniques, and increasingly these techniques are being employed in the diagnosis and treatment of a wide range of malignancies. This book is designed to serve as a unique and comprehensive overview of the current status of minimally invasive surgery in oncology patients and in addition offers valuable insights into the future of this constantly evolving field. The first section of the book is devoted to essential background information and to explaining what is physiologically distinctive in the cancer patient undergoing laparoscopic surgery. The second section then examines in detail a wide range of clinical aspects and issues across different disciplines, with clear instruction on the use of minimally invasive procedures. The aim is to enable the reader to make treatment decisions appropriate to the individual patient, to carry them out effectively, and to institute suitable postoperative care. Summaries of the latest knowledge in traditional therapies such as chemotherapy are also provided when appropriate. Each chapter is written by a recognized expert, and numerous high-quality illustrations are included to assist understanding. This book will serve both as a clinical reference guide and as an operative atlas, and is certain to prove invaluable in daily clinical practice.

"Minimally Invasive Therapy for Urinary Incontinence and Pelvic Organ Prolapse provides a detailed insight into "when, why, what and how" of various minimally invasive surgical procedures for surgical management of SUI, OAB & POP. The volume provides detailed diagrammatic and pictorial step-by-step descriptions of the techniques and management of complications related to these procedures. This book also presents an up to date, one-stop reference for anything pertaining to MIT of these pelvic disorders. Written by experts in the field, Minimally Invasive Therapy for Urinary Incontinence and Pelvic Organ Prolapse is a comprehensive resource designed for both the urologist and urogynecologist treating patients with urinary disorders and pelvic organ prolapsed, as well as for residents in training."--Publisher's website.

This book describes in detail the various techniques of minimally invasive thyroidectomy that have emerged in recent years and presents the new supportive equipment, including intraoperative monitoring and energy devices. In addition, the basic preoperative techniques that are a prerequisite to successful thyroidectomy are covered, and individual chapters are devoted to complications, outcomes, and post-thyroidectomy quality of life. Important related topics are also discussed, including guidelines for managing papillary and medullary thyroid cancer and the surgical management of metastatic lymph nodes. Both the editors and the authors are internationally renowned experts, and they include the founders of several of the techniques described. The up-to-date text is supplemented by many color pictures and medical illustrations, making the book very user-friendly and ideal for the busy surgeon or endocrinologist who is interested in the management of thyroid diseases.

"The United States health care system is the most expensive in the world, but comparative analyses consistently show the U.S. underperforms relative to other countries on most dimensions of performance. Among the 11 nations studied in this report --Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States -- the U.S. ranks last, as it did in prior editions of Mirror, Mirror. The United Kingdom ranks first, followed closely by Switzerland. Since the data in this study were collected, the U.S. has made significant strides adopting health information technology and undertaking payment and delivery system reforms spurred by the Affordable Care Act. Continued implementation of the law could further encourage more affordable access and more efficient organization and delivery of health care, and allow investment in preventive and population health measures that could improve the performance of the U.S. health care system."--Abstract.

The federally facilitated health insurance marketplace (FFM) is attempting to improve consumers' ability to make plan-to-plan comparisons during the 2017 open enrollment season by encouraging insurers to offer standardized benefit designs. In doing so, the FFM is following the path of several state-based marketplaces (SBMs) that require insurers to offer standardized health plans, although the FFM and most SBMs also allow insurers to offer nonstandardized options. Through an analysis of policy guidance, consumer-facing marketplace websites, and interviews with state officials and key stakeholders, this paper explores the experiences of SBMs in Connecticut, Massachusetts, New York, and Oregon that have required participating insurers to offer standardized plans. The authors find that although broad consensus exists among state officials and stakeholders that the primary goal of health plan standardization is to facilitate "apples-to-apples" plan comparisons, these states' policy choices and website interfaces have curtailed their ability to achieve these stated goals. In particular, by allowing insurers to offer nonstandardized options in addition to standardized options and failing to use web-based decision support tools to differentiate between plan options, consumers in these SBMs have limited ability to conduct the plan-to-plan comparisons as originally envisioned by policymakers.

While directed cellular migration facilitates the coordinated movement of cells throughout development, in wound repair, and during an immune response, the precise mechanisms regulating such migration in vivo remain inadequately understood. Missing in Metastasis (MIM) is a defining member of the I-BAR subfamily of lipid binding, actin cytoskeletal regulators whose levels are altered in a number of cancers. Here I provide the first genetic evidence that I-BAR proteins regulate directed cell migration in vivo. MIM regulates the directional migration of several cell types responding to a number of different guidance cues. While regulating the directionality of migrating cells has been demonstrated in vitro, this role of an I-BAR protein in vivo was not previously observed. I demonstrate in these studies that Drosophila MIM (DMIM) is required for border cell migration, with loss of dmim function resulting in a lack of directional movement by the border cell cluster. In vivo endocytosis assays combined with genetic analyses demonstrate that the dmim product regulates directed cell movement by inhibiting endocytosis and antagonizing the activities of the endophilin/CD2AP/cortactin complex in these cells. These studies demonstrate that competition between BAR family members for pro-endocytic components underlies a directional sensing mechanism during guided cell migration.

Part 1. General principles of mitochondria and the heart -- Introduction to Mitochondria in the Heart -- Methods to Study Mitochondrial Structure and Function -- Mitochondrial Structure, Composition, and Dynamics -- Mitochondrial Biogenesis -- Mechanisms of Bioenergy Production in Mitochondria -- Bioenergetics Interplay Between Cardiac Mitochondria and Other Subcellular Compartments -- Part 2. Heart mitochondria signal transduction. Stem cells -- Endothelial Mitochondria: Contribution to Cardiovascular Function and Disease -- Heart Mitochondria: Receivers and Transmitters of Signals -- Stem Cells and Mitochondria -- Part 3. Stress and cell death -- Heart Mitochondrial ROS and Oxidative Stress -- Cell-Death Pathways and Mitochondria -- Part 4. Mitochondria in Pediatric Cardiology -- Mitochondria in Pediatric Cardiovascular Diseases -- Part 5. The aging heart and mitochondria -- Mitochondria in the Aging Heart -- Part 6. Mitochondria in Atherosclerosis, hypertension and ischemia -- The Role of Mitochondria in Atherosclerosis -- The Role of Mitochondria in Hypertension -- Role of Mitochondria in Ischemia and Cardioprotection -- Part 7. Mitochondria in Heart Failure and Dysrhythmias -- Mitochondrial Dynamics in Health and Disease -- Mitochondria Play an Essential Role in Heart Failure -- Mitochondria and Cardiac Dysrhythmias -- Part 8. Mitochondria in heart metabolism -- Diabetes and Cardiac Mitochondria -- The Role of Mitochondria in the Metabolic Syndrome and Insulin Resistance -- Thyroid Hormone and Myocardial Mitochondria -- Part 9. Mitochondrial Therapy -- Targeting the Mitochondria in Cardiovascular Diseases -- Part 10. Looking to the future of mitochondria and the heart -- Current Progress and Future Perspectives: Toward Mitochondrial Medicine.

This book highlights the importance of phytochemicals and mitochondria in cancer prevention and therapy. Recent scientific discoveries have identified that naturally occurring biologically active compounds (i.e. phytochemicals) target multiple steps of tumorigenesis leading to the inhibition or delay in cancer progression. Mitochondria, organelles within a cell, are a critical target for phytochemicals in regulating the initiation, promotion, and progression of cancer.

Protozoan and prokaryotic pathogens are able to recruit mitochondria to the vacuoles in which they grow (Friis, 1972; Horwitz, 1983), in mammalian and protozoan cells. The functional significance of the recruitment and association of this phenomenon in Toxoplasma-infected cells has been a subject of speculation since it was first described in the early 1970s (Jones et al., 1972). Previous work has proposed Toxoplasma gondii rhoptry protein 2 (Sinai and Joiner, 2001) as the physical link that tethers host mitochondria to the parasitophorous vacuole and conventional wisdom since has suggested that mitochondrial recruitment served a nutritional function supplementary to the parasite. A recent analysis of the ROP2 structure raised questions about this model ((Labesse et al., 2009; Reese and Boothroyd, 2009). Chapter II describes the effect of deleting ROP2 on mitochondrial association while Chapter III describes the identification of a novel mediator of mitochondrial association, Mitochondrial association factor I (MAF1) and experiments that attempt to answer the role of this remarkable phenomenon in the host-pathogen interaction. Chapter IV describes a project undertaken to determine the impact of Toxoplasma gondii infection in humans acutely and chronically infected in different geographical regions. Chapter V concludes with a discussion of future directions for further characterization of host mitochondrial association in the host response to microbial infection.

Mitochondrial cytopathies are mutations in the inherited maternal mitochondrial genome, or the nuclear DNA-mutation. Mitochondrial respiratory chain disorders (RCD) are a group of genetically and clinically heterogeneous diseases, due to the fact that protein components of the respiratory chain are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure and function of mitochondria, including DNA replication, transcription, and translation, all require nuclear encoded genes. Since mitochondria are present in every cell, every tissue, mitochondrial disorders usually affects multiple organs. Mitochondrial Disorders Caused by Nuclear Genes discusses the biochemical, molecular, clinical, and genetic aspects of complex dual genome mitochondrial disorders. Chapters include genes involved in mitochondrial DNA biogenesis and maintenance of mitochondrial DNA integrity, complex subunits and assembly genes, and mitochondrial protein translation related diseases.

"This text covers the basic principles of mitochondrial dynamics in cardiovascular medicine, with particular emphasis on their functional roles in physiology and disease. The book will include articles pertaining to mitochondrial fitness on a global basis, providing therefore an update on the progress made in several aspects in the field. Thus, it will assist scientists and clinicians alike in furthering basic and translational research. Organized in sections focusing on: basic science, mitochondrial dysfunction in cardiac disorders, in vascular disorders, in metabolic disorders, in kidney disease, therapeutic challenges and options, this essential volume fills imperative gaps in understanding and potentially treating several cardiovascular disorders"--Publisher's description.

Mitochondria, often referred to as the 'powerhouses' of the cell, generate adenosine triphosphate (ATP) by oxidative phosphorylation or OXPHOS, and maintain cellular homeostasis. In addition to generating ATP, mitochondria are involved in regulation of cell cycle, proliferation, free radical production, innate immune responses and apoptosis. Mitochondrial Function in Lung Health and Disease fills the current gap in the literature and outlines the growing clinical relevance of mitochondrial dysfunction. Currently, there is no overview on the role of mitochondria in pulmonary diseases and this volume focuses on the mitochondrial metabolism, redox signaling, and mechanisms of mitochondrial pathways in lung injury, inflammation, repair and remodeling. Furthermore, in addition to their well-recognized role in cellular energy production and apoptosis, mitochondria appear to play a role in many respiratory diseases and lung cancer. Chapters are written by top notch researchers and clinicians and outline the evidence for mitochondrial biogenesis in inhalational lung injury, COPD and asthma.

This expert volume covers an interdisciplinary and rapidly growing area of biomedical research comprising genetic, biochemical, pathological, and clinical studies aimed at the diagnosis and therapy of human diseases which are either caused by or associated with mitochondrial dysfunction. It dedicates itself to showcasing the tremendous efforts and the progress that has been made over the last decades in developing techniques and protocols for probing, imaging, and manipulating mitochondrial functions. "Mitochondrial Medicine: Volume I, Probing Mitochondrial Function" focuses on methods being used for the assessment of mitochondrial function under physiological conditions as well as in healthy isolated mitochondria. Written in the highly successful "Methods in Molecular Biology" series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.Comprehensive and practical, "Mitochondrial Medicine" provides an essential source of know-how and inspiration to all researchers who are fascinated by this tiny organelle that seems so clearly to control the life and death of a single cell and whole organisms alike.

This expert volume covers an interdisciplinary and rapidly growing area of biomedical research comprising genetic, biochemical, pathological, and clinical studies aimed at the diagnosis and therapy of human diseases which are either caused by or associated with mitochondrial dysfunction. It dedicates itself to showcasing the tremendous efforts and the progress that has been made over the last decades in developing techniques and protocols for probing, imaging, and manipulating mitochondrial functions. "Mitochondrial Medicine: Volume II, Manipulating Mitochondrial Function" describes techniques developed for manipulating and assessing mitochondrial function under general pathological conditions and specific disease states. Written in the highly successful "Methods in Molecular Biology" series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.Comprehensive and practical, "Mitochondrial Medicine" provides an essential source of know-how and inspiration to all researchers who are fascinated by this tiny organelle that seems so clearly to control the life and death of a single cell and whole organisms alike.

"This book examines a unique assembly of coordinated mitochondrial functions that are important in regulating cell function and are of relevance in a myriad of pathophysiological situations, such as age-related neurodegenerative disorders, cancer, metabolic syndrome, and cardiovascular disease. The text covers themes essential for the maintenance of mitochondrial activity, including electron transport and energy production, mitochondrial biogenesis and dynamics, mitochondrial signaling, and apoptosis and autophagy. The book features chapters that are reviews of the important topics covered and are written by an impressive cadre of internationally recognized scientist"--Provided by publisher.

Evolutionary adaptation is a process in which beneficial mutations increase in frequency in response to selective pressures. If these mutations were previously rare or absent from the population, adaptation should generate a characteristic signature in the genetic diversity around the adaptive locus, known as a selective sweep. Such selective sweeps can be distinguished into hard selective sweeps, where only a single adaptive mutation rises in frequency, or soft selective sweeps, where multiple adaptive mutations at the same locus sweep through the population simultaneously. In my second chapter, I propose two new statistics, H12 and H2/H1, which can identify and differentiate hard and soft sweeps in population genomic data. I apply this method to a Drosophila melanogaster population genomic dataset consisting of 145 sequenced strains collected in North Carolina and find that selective sweeps were abundant in the recent history of this population. Interestingly, I also find that practically all of the strongest and most recent sweeps show patterns that are more consistent with soft rather than hard sweeps. In my third chapter, I demonstrate an inverse relationship between H12 and H2/H1 and develop an upper bound for H2/H1 as a function of H12. This upper bound can be used to normalize H2/H1, which can facilitate the interpretation of the application of H12 and H2/H1 to heterogenous data. Finally, in my fourth chapter, I find that the patterns of abundant soft selective sweeps are not unique to the North Carolina data set and are present in a population sample of 200 individuals from Zambia. These results together suggest that adaptation can be rapid in multiple populations of D. melanogaster.

"The Ndlovu Care Group (NCG), a South African NGO, provides health care and community care for people living in a rural area of South Africa, in particular the Moutse area in Limpopo and Mpumalanga provinces. There are 120,000 to 150,000 beneficiaries. In a period of 15 years, Hugo Tempelman and co-workers developed an integrated model of care serving the broad health and community needs of poor people in an area where almost no medical and health care services are provided. This book describes a model for the advancement of rural areas in South Africa through community health and community care as developed by NCG. Over the years it became evident that this model could have an impact on the further advancement of rural areas in any developing country. NCG operates through two divisions, the Autonomous Treatment Centre (ATC) and the Community Health Awareness Mobilisation & Prevention (CHAMP) programme. The ATC is an extended community health centre that provides integrated primary health, TB and HIV/AIDS care and treatment, including maternal and reproductive health care and advanced HIV/AIDS in-patient care. The co-operation with governmental departments is described. The CHAMP programme consists of an AIDS awareness programme for schools, farms and local communities; programmes for vulnerable children because of e.g. HIV & AIDS infection, under- and malnourishment, disturbed family life, death of parents; a dental programme; art, culture and sports activities; all kinds of community activities, like a waste programme, a nappy factory and an IT training programme; and an environmental awareness and education programme. NCG has established its care model in two rural locations in South Africa, and is in the process of developing two more sites. To show the validity of its work, it also carries out monitoring & evaluation procedures and evidence-based research. Several chapters of this book testify to this scientific approach."--Back cover.

Malignant tumors due to breast cancer and masses due to benign disease appear in mammograms with different shape characteristics: the former usually have rough, spiculated, or microlobulated contours, whereas the latter commonly have smooth, round, oval, or macrolobulated contours. Features that characterize shape roughness and complexity can assist in distinguishing between malignant tumors and benign masses. In spite of the established importance of shape factors in the analysis of breast tumors and masses, difficulties exist in obtaining accurate and artifact-free boundaries of the related regions from mammograms. Whereas manually drawn contours could contain artifacts related to hand tremor and are subject to intra-observer and inter-observer variations, automatically detected contours could contain noise and inaccuracies due to limitations or errors in the procedures for the detection and segmentation of the related regions. Modeling procedures are desired to eliminate the artifacts in a given contour, while preserving the important and significant details present in the contour.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and akinesia which affects approximately 1% of the population over the age of 60. These motor symptoms result from the selective destruction of midbrain dopamine (DA) neurons which form the nigrostriatal pathway. While there is likely to be a diverse range of inciting factors across patients, common pathological pathways mediating the selective loss of substantia nigral dopaminergic neurons are predicted. Only a small fraction of all PD cases can be ascribed to monogenic causes, however, these mutations provide our best chance for making progress in understanding PD pathophysiology. The accumulation and aggregation of alpha-synuclein (SNCA) in the form of Lewy bodies and Lewy neurites are defining neurocytological hallmarks for PD, suggesting that SNCA may be a linchpin to PD pathology. Duplications and triplications of SNCA are autosomal dominant causes of PD, and overexpression of SNCA has also recapitulated certain disease characteristics in animal and cell models. Mutations in the leucine rich repeat kinase 2 (LRRK2) are also implicated in PD pathogenesis. LRRK2 is predicted to interact either directly or indirectly with SNCA. Indeed, LRRK2 mutations are predicted to cause increased SNCA expression. As PD is only known to naturally occur in humans, and selectively targets midbrain DA neurons, a human midbrain DA neuron model involving known monogentic mutations would be a powerful platform for examining disease pathology. Here we describe the generation of induced pluripotent stem cells (iPSCs) created from patients with PD stemming from either an SNCA triplication (Trpl) or a G2019S mutation in LRRK2 (Lrkm). Human dopamine neuron cultures from these genetically-defined PD patients demonstrated overt pathological phenotypes. Both Trpl and Lrkm DA neuronal cultures contained an accumulation of monomeric SNCA, and markers of oxidative stress as compared to control embryonic stem cell (ESC) or iPSC lines. Trpl DA neuronal cultures possessed a marked increase in cells laden with ubiquitin puncta as compared to sibling control lines. Lrkm DA neuronal cultures were more susceptible to both the general oxidative stressor H2O2 and the selective DA neurotoxin 6-OHDA. These and other similarly derived lines will provide a powerful platform for investigating the molecular events in PD, and will enable large-scale screening for new therapeutic compounds to prevent and halt the progression of PD. While a fraction of all PD cases have known monogenic correlates, the majority cases are sporadic, with no recognized cause. In these cases, PD cannot be predicted and diagnosis is only made following the onset of symptoms, so even with significant advances in halting the progression of DA neuronal loss, there is and will continue to be a need for late-stage treatment options. Transplantation of human DA neurons is one such option. While most prior transplantation models for PD therapy graft cells directly into the target striatum, it should be remembered that DA neurons are part of a circuit, so ideal transplantation would graft DA neurons into the striatum and coax them to innervate the striatum thus rebuilding the native circuit. A major challenge to this type of advanced transplantation is the ability to accurately control the outgrowth and guidance of DA neurites. This requires detailed knowledge of the axon guidance cues that these particular neurons normally respond to, and how these responses may change in the context of severe neuroinflammation present in the diseased and post-op brain. Utilizing an in-vitro COS-cell aggregate outgrowth assay, we demonstrate that ESC-derived human midbrain DA neurons are attracted to gradients of netrin-1 and repelled by gradients of slit-2 in a manner that is similar to primary rat midbrain DA neurons. While these responses were not abolished in the presence of inflammatory cytokines, the response to netrin-1 was modified. These findings suggest that the outgrowth and innervation of transplanted human ESC/iPSC-derived DA neurons may be targeted by application of exogenous guidance factors, or manipulation of endogenous guidance factors and inflammatory cytokines in order to achieve better therapeutic outcomes. Further development these of human ESC and iPSC derived midbrain DA neuron models are likely to lead to major advances in our understanding of the basic developmental and functional neurobiology of DA neurons, and how these features are disrupted in disease processes like PD.

Phase transitions in single neurons and neural populations: Critical slowing, anesthesia, and sleep cycles -- Generalized state-space models for modeling nonstationary EEG time-series -- Spatiotemporal instabilities in neural fields and the effects of additive noise -- Spontaneous brain dynamics emerges at the edge of instability -- Limited spreading: How hierarchical networks prevent the transition to the epileptic state -- Bifurcations and state changes in the human alpha rhythm: Theory and experiment -- Inducing transitions in mesoscopic brain dynamics -- Phase transitions in physiologically-based multiscale mean-field brain models -- A continuum model for the dynamics of the phase transition from slow-wave sleep to REM sleep -- What can a mean-field model tell us about the dynamics of the cortex? -- Phase transitions, cortical gamma, and the selection and read-out of information stored in synapses -- Cortical patterns and gamma genesis are modulated by reversal potentials and gap-junction diffusion.

This practical introduction to molecular modelling of GPCRs covers core principles, and moves on to present advanced GPCR modelling techniques. Includes data on crystal structures and essential amino acid sequences, as well as LINUX commands and examples.

In today's nanotechnology and pharmaceutical research, alternative toxicology testing methods are crucial for ethically and commercially sound practice. This book provides practical guidelines on how to develop and validate quantitative nanostructure-toxicity relationship (QNTR) models, which are ideal for rapidly exploring the effects of a large number of variables in complex scenarios. Through contributions by academic, industrial, and governmental experts, Modelling the Toxicity of Nanoparticles delivers clear instruction on these methods and their integration and use in risk assessment. Specific topics include the physico-chemical characteristics of engineered nanoparticles, nanoparticle interactions, in vivo nanoparticle processing, and more. A much-needed practical guide, Modelling the Toxicity of Nanoparticles is a key text for researchers as well as government and industry regulators.

There are five different types of eye movements: saccades, smooth pursuit, vestibular ocular eye movements, optokinetic eye movements, and vergence eye movements. The purpose of this book series is focused primarily on mathematical models of the horizontal saccadic eye movement system and the smooth pursuit system, rather than on how visual information is processed. A saccade is a fast eye movement used to acquire a target by placing the image of the target on the fovea. Smooth pursuit is a slow eye movement used to track a target as it moves by keeping the target on the fovea. The vestibular ocular movement is used to keep the eyes on a target during brief head movements. The optokinetic eye movement is a combination of saccadic and slow eye movements that keeps a full-field image stable on the retina during sustained head rotation. Each of these movements is a conjugate eye movement, that is, movements of both eyes together driven by a common neural source. A vergence movement is a non-conjugate eye movement allowing the eyes to track targets as they come closer or farther away. In Part 1, early models of saccades and smooth pursuit are presented. A number of oculomotor plant models are described therein beginning with the Westheimer model published in 1954, and up through our 1995 model involving a 4th-order oculomotor plant model. In Part 2, a 2009 version of a state-of-the-art model is presented for horizontal saccades that is 3rd-order and linear, and controlled by a physiologically based time-optimal neural network. In this book, a multiscale model of the saccade system is presented, focusing on the neural network. Chapter 1 summarizes a whole muscle model of the oculomotor plant based on the 2009 3rd-order and linear, and controlled by a physiologically based time-optimal neural network. Chapter 2 presents a neural network model of biophysical neurons in the midbrain for controlling oculomotor muscles during horizontal human saccades. To investigate horizontal saccade dynamics, a neural circuitry, including omnipause neuron, premotor excitatory and inhibitory burst neurons, long lead burst neuron, tonic neuron, interneuron, abducens nucleus, and oculomotor nucleus, is developed. A generic neuron model serves as the basis to match the characteristics of each type of neuron in the neural network. We wish to express our thanks to William Pruehsner for drawing many of the illustrations in this book.

There are five different types of eye movements: saccades, smooth pursuit, vestibular ocular eye movements, optokinetic eye movements, and vergence eye movements. The purpose of this book is focused primarily on mathematical models of the horizontal saccadic eye movement system and the smooth pursuit system, rather than on how visual information is processed. A saccade is a fast eye movement used to acquire a target by placing the image of the target on the fovea. Smooth pursuit is a slow eye movement used to track a target as it moves by keeping the target on the fovea. The vestibular ocular movement is used to keep the eyes on a target during brief head movements. The optokinetic eye movement is a combination of saccadic and slow eye movements that keeps a full-field image stable on the retina during sustained head rotation. Each of these movements is a conjugate eye movement, that is, movements of both eyes together driven by a common neural source. A vergence movement is a non-conjugate eye movement allowing the eyes to track targets as they come closer or farther away. In this book, early models of saccades and smooth pursuit are presented. The smooth pursuit system allows tracking of a slow moving target to maintain its position on the fovea. Models of the smooth pursuit have been developed using systems control theory, all involving a negative feedback control system that includes a time delay, controller and plant in the forward loop, with unity feedback. The oculomotor plant and saccade generator are the basic elements of the saccadic system. The oculomotor plant consists of three muscle pairs and the eyeball. A number of oculomotor plant models are described here beginning with the Westheimer model published in 1954, and up through our 1995 model involving a 4th order oculomotor plant model. The work presented here is not an exhaustive coverage of the field, but focused on the interests of the author. In Part II, a state-of-art model of the saccade system is presented, including a neural network that controls the system.

There are five different types of eye movements: saccades, smooth pursuit, vestibular ocular eye movements, optokinetic eye movements, and vergence eye movements. The purpose of this book is focused primarily on mathematical models of the horizontal saccadic eye movement system and the smooth pursuit system, rather than on how visual information is processed. A saccade is a fast eye movement used to acquire a target by placing the image of the target on the fovea. Smooth pursuit is a slow eye movement used to track a target as it moves by keeping the target on the fovea. The vestibular ocular movement is used to keep the eyes on a target during brief head movements. The optokinetic eye movement is a combination of saccadic and slow eye movements that keeps a full-field image stable on the retina during sustained head rotation. Each of these movements is a conjugate eye movement, that is, movements of both eyes together driven by a common neural source. A vergence movement is a non-conjugate eye movement allowing the eyes to track targets as they come closer or farther away. In this book, a 2009 version of a state-of-the-art model is presented for horizontal saccades that is 3rd-order and linear, and controlled by a physiologically based time-optimal neural network. The oculomotor plant and saccade generator are the basic elements of the saccadic system. The control of saccades is initiated by the superior colliculus and terminated by the cerebellar fastigial nucleus, and involves a complex neural circuit in the mid brain. This book is the second part of a book series on models of horizontal eye movements.

Millions of procedures requiring sedation are performed each year, covering a large array of medical specialties in both inpatient and outpatient settings. This tremendous growth has led to sedation being administered by a wide range of healthcare providers, including non-anesthesiologist physicians, nurses and nurse practitioners. Moderate and Deep Sedation in Clinical Practice is a concise, practical handbook for all medical and surgical professionals who sedate patients. This up-to-date, evidence-based 'how-to' manual instructs these professionals on how to evaluate patients, updates relevant pharmacology, and guides them on legal and quality assurance issues. It contains advice on sedation for specific populations, such as elderly, pediatric, ICU, emergency room, endoscopy, and reproductive technologies. Written and edited by experts in procedural sedation and sedation education, this book will help users develop safer techniques, policies, and procedures. It is essential reading for any healthcare provider administering moderate or deep sedation.

This volume covers classic as well as cutting-edge topics on the analysis of clinical trial data in biomedical and psychosocial research and discusses each topic in an expository and user-friendly fashion. Starting with survival data analysis, this book transitions from such a classic topic to modern issues by stepping through diagnostic test and instrument assessment, sequential and dynamic treatment regimen, cost-effectiveness evaluation, equivalence testing. As some type of cancer such as the effect of smoking on lung cancer cannot be studied using randomized trials, a chapter on analysis of non-randomized studies is also included. The book concludes with a chapter discussing the opportunities and challenges that lie ahead in developing on person-centered treatment regimens. The book provides an overview of the primary statistical and data analytic issues associated with each of the selected topics, followed by a discussion of approaches for tackling such issues and available software packages for carrying out the analyses. Medical researchers with some background in clinical trial design and regression analysis as well as biostatisticians will find this book informative and helpful.

Recognized as an essential component of Chinese culture, Traditional Chinese Medicine (TCM) is both an ancient medical system and one still used widely in China today. TCM's independently evolved knowledge system is expressed mainly in the Chinese language and the information is frequently only available through ancient classics and confidential family records, making it difficult to utilize. The major concern in TCM is how to consolidate and integrate the data, enabling efficient retrieval and discovery of novel knowledge from the dispersed data. Computational approaches such as data mining, semantic reasoning and computational intelligence have emerged as innovative approaches for the reservation and utilization of this knowledge system. Typically, this requires an inter-disciplinary approach involving Chinese culture, computer science, modern healthcare and life sciences. This book examines the computerization of TCM information and knowledge to provide intelligent resources and supporting evidences for clinical decision-making, drug discovery, and education. Recent research results from the Traditional Chinese Medicine Informatics Group of Zhejiang University are presented, gathering in one resource systematic approaches for massive data processing in TCM. These include the utilization of modern Semantic Web and data mining methods for more advanced data integration, data analysis and integrative knowledge discovery. This book will appeal to medical professionals, life sciences students, computer scientists, and those interested in integrative, complementary, and alternative medicine. Interdisciplinary book bringing together Traditional Chinese Medicine and computer scientists. Introduces novel network technologies to Traditional Chinese Medicine informaticsProvides theory and practical examples and case studies of new techniques.

Modern Electroencephalographic Assessment Techniques: Theory and Applications presents numerous signal processing and connectivity analysis methodologies addressing a wide variety of clinical applications including epilepsy, schizophrenia, Alzheimer's disease and even alcoholism. Among the different topics addressed, the neurophysiological basis of cognitive processes is also investigated. The goal is to provide a comprehensive overview of the most modern and widely established approaches mainly applied in, but not limited to, decomposing high resolution multichannel Electroencephalography (EEG) and Magnetoencephalography (MEG) signals into functional interconnected brain regions. Synergistic approaches linking both EEG/ MEG and functional Magnetic Resonance Imaging (fMRI) techniques are also discussed. In line with the popular Neuromethods series, chapters present the theoretical basis of each method along with prosperous application domains, in the form of a balanced mixture of theoretical tutorials, comprehensive reviews and original research. Emphasis is given to the underlying assumptions, to technical matters that greatly affect the outcome of each proposed method, to the ambitions and to the domain of application of each method. Furthermore, links to graph theory and visualization of connectivity motifs is also addressed in an attempt to better describe the functional characteristics of brain networks.Authoritative and practical, Modern Electroencephalographic Assessment Techniques: Theory and Applications touches upon both the biomedical and computational aspects of this exciting and rapidly evolving field and will allow for a more in-depth, vital understanding of the brain's complex underlying mechanisms.

'Modern Misogyny' examines contemporary antifeminism in a 'postfeminist' era. It considers the widespread idea that the feminist movement has ended, it achieved what it set out to achieve and is irrelevant to contemporary women's lives. The book argues that equality has not been achieved and that sexism and discrimination are now packaged in a more palatable but stealthy form.

Humans can resist 40 days without eating and 4 days without drinking, but only 4 minutes without breathing: this tells us much about its fundamental importance. Breathed air is slowed down, filtered, warmed and humidified by the nose; many mechanisms are involved in this act, which prevent bronchial tubes and pulmonary alveolus from receiving an excessive and sudden air load. It is well known, on the other hand, that breathing through the mouth causes a lot of problems: inflammatory diseases of the upper airways, sleep apnea syndrome, but also, in some cases, bronchial, pulmonary and even cardiac disorders, that are more easily affecting patients not able to breathe correctly through the nose. For this reason, restoring an efficient nasal function is a very important - and in some cases crucial - issue. This book describes in details an innovative surgical technique called modified inferior turbinoplasty, which offers an excellent solution to the problems associated with the lower turbinate hypertrophy. A turbinate (or nasal concha) is a long, narrow, curled bone shelf that protrudes into the breathing passage of the nose. Most surgical interventions treat only the soft parts of hypertrophic turbinates using laser therapy, radiofrequency treatment, and electrocoagulation, but these procedures often lead to relapse. With this technique, in contrast, all anatomic parts of the turbinate are treated, including bone tissue: the surgeon reduces the inferior nasal concha and the internal nasal tissue, and the mucosa is then remodeled with sutures. The modified inferior turbinoplasty allows the complete avoidance of swabs in the nose, which is fundamental for patients well-being and grant them a quicker recovery. The book will be very useful for othorinolaryngologists, plastic surgeons, endoscopic and maxillofacial surgeons.

This thesis discusses a number of projects involving the use of modified nucleotides and oligonucleotides in addressing some basic science questions and some clinical and technological applications.The first chapter details our efforts at using telomere-encoding circular DNA in elongating zebrafish telomeres. We microinjected our synthetic circular DNA into zebrafish embryos and studied their telomere length 24 hrs later. Using Quantitative Fluorescence in situ Hybridization (Q-FISH) as the analytical tool to determine telomere length, we observed no significant difference in telomere length between the group injected with the synthetic DNA and the control group. In the second chapter we studied the potential of a non-polar shape mimic of iodo-uracil as an imager of tumors. We continued discussing our work with non-polar nucleotide isosteres in the third chapter where we used them in investigating a novel active site in polymerase from Pyrococcus furiosus (Pfu). From our studies we concluded that although shape was an important factor in distinguishing bases, this binding site also employed hydrogen bonding to identify nucleoabases. The lack of any recognition of the syn-oxidized bases suggested that the enzyme preferred to recognize bases in the anti conformation rather than syn. In the fourth chapter we were interested in understanding the factors determining the fidelity and selectivity observed in RNA Polymerase II mediated transcription. Once again we used non-polar shape mimics of thymidine (dF) and adenine (dQ) to study the importance of shape and hydrogen bonding. We observed that the thymidine mimic was recognized better by the RNA Polymerase II active site than the mis-match bases. The adenine isostere on the other hand, was poorly recognized. This preliminary study demonstrates the importance of both shape and hydrogen bonding. The last chapter discusses our studies using polyfluorophores on a DNA backbone to detect gases. Following a combinatorial method, a library of oligodeoxyfluorosides (ODFs) were synthesized from which sensors of gases were selected. Using this method we were able to select optical sensors for a diverse set of small molecules in vapor state.

Growing evidence indicates that cancers are composed of functionally heterogeneous cells that are organized by a cellular hierarchy and are maintained by a stem cell-like population. Given their unique ability to initiate tumor growth, eradication of these cancer stem cells (CSC) is necessary for cure. Thus, the development of CSC targeted therapies is necessary to improve current clinical outcomes. This body of work identifies CD47 as a therapeutic target on CSC and bulk cells in several human malignancies. CD47 is a cell surface protein that functions to inhibit phagocytosis through binding its ligand SIRP[Alpha], expressed on phagocytes. Compared to normal cell counterparts, CD47 was highly expressed on several human tumors including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL), suggesting that higher CD47 levels on tumors allow evasion of immune phagocytosis. Higher CD47 expression in these tumors correlated with a worse clinical prognosis and was an independent prognostic factor. Furthermore, a monoclonal blocking antibody against CD47 enabled phagocytosis of human AML, ALL, and NHL in vitro and eliminated disease in vivo. When combined with the Fc receptor-activating antibody, rituximab, anti-CD47 antibody therapy achieved high cure rates in pre-clinical models of NHL in contrast to partial responses with either agent alone. Lastly, anti-CD47 antibody treatment specifically targeted tumor but not normal cells, resulting in minimal toxicity in vitro and in vivo. The selective targeting of tumor cells by anti-CD47 antibody was due to the selective expression of the pro-phagocytic signal, calreticulin on tumor but not normal cells. In summary, this body of work identifies CD47 as a therapeutic target on several human cancers and that a monoclonal blocking antibody against CD47 has pre-clinical efficacy in eliminating these tumors through the promotion of phagocytosis.

Hepatitis C virus (HCV) is a global health problem, infecting approximately 2% of the world's population. The virus is hepatotropic, replicating in liver cells, and its only known hosts are humans and chimpanzees. HCV is an unusual virus in that it requires the liver-specific host microRNA (miRNA) miR-122 for HCV RNA accumulation. Though the precise mechanism by which miR-122 upregulates HCV RNA is still under investigation, it is known that miR-122 must bind to two adjacent sites in the 5' end of the HCV genome. In this dissertation, a stepwise mutational analysis of the entire sequence of miR-122 was performed to identify residues important for HCV RNA accumulation. All mutant miRNAs were tested in canonical miRNA reporter assays and in HCV RNA accumulation assays. The identities of two nucleotides within miR-122, at positions 15 and 16, were shown to be dispensable for canonical miRNA and siRNA activity but required for HCV RNA accumulation. Compensatory mutations in the HCV genome upstream of the original binding sites uncovered supplementary binding sites for nucleotides 15 and 16 of miR-122. This analysis led to a new model for miR-122-HCV RNA interactions. To further define the requirements of HCV for miR-122, we investigated whether the predecessor of mature miR-122, a long hairpin precursor designated pre-miR-122, was also able to mediate HCV RNA accumulation. The function of pre-miR-122 was tested in miRNA, siRNA, and HCV RNA accumulation assays. Inhibition of pre-miR-122 processing was achieved by substituting deoxyribonucleotides into the loop of pre-miR-122 to prevent Dicer-mediated cleavage. Full-length pre-miR-122 was demonstrated to be functional in miRNA and siRNA assays and to be sufficient for HCV RNA accumulation. Pre-miR-122 also required traditional components of the RNA-induced silencing complex (RISC) for activity. Taken together, this research has uncovered novel requirements of miR-122 for HCV RNA accumulation. Components shown to be dispensable for canonical miRNA interactions were necessary for this unusual microRNA-target RNA interaction. Uncovering hepatitis C virus's stringent requirements for the mature and precursor forms of miR-122 will pave the way for new antiviral therapies targeting a host factor.

"This book brings together leading international experts to discuss recent advances in the regulation of presynaptic voltage-gated Ca2+ channels (VGCCs), key signal transducers that represent one of the most widely modulated proteins in the body. It is now commonly accepted that presence of the VGCC complex defines an excitable cell. At a basic level, VGCCs transduce membrane potential change to chemical neurotransmitter release at presynaptic terminals. However, on-going scientific research, presented here, in areas including neuroscience, electrophysiology, pharmacology, biochemistry and, increasingly, proteomics, has revealed the widespread nature of modulation of the presynaptic VGCC complex. This book reviews and discusses the following topics: The fundamental role of the VGCC pore-forming CaVa subunit, and some of their binding partners, in presynaptic function and synaptic plasticity. Modulation of presynaptic CaVa subunits by auxiliary CaVb and a2d subunits and by their major interaction partners, such as active zone scaffolding proteins, synaptic proteins, G proteins and small GTPases, which, together, contribute to the VGCC proteome. Work at the cutting edge of research, including how direct electrophysiology recordings from presynaptic terminals and introduction of synthetic CaVa peptides into presynaptic terminals has expanded our knowledge of VGCC function. Evidence emerging over the last decade demonstrating that VGCC subunits represent bona fide molecular targets for therapeutic drug discovery. This development is illustrated by the introduction of the CaV2.2 blocker ziconotide, which represents an important proof-of-concept, but is best exemplified by the emergence of gabapentinoids, which bind the VGCC auxiliary a2d subunit, as first-line treatments for chronic neuropathic pain. Throughout, chapters are accompanied with illustrative Tables and Figure providing a useful and comprehensive summary of the current state-of-play in this area of significant therapeutic interest. Work described here also provides a solid basis for future research in this important area." -- Back cover.

Mannose 6-phosphate receptors (MPRs) deliver lysosomal acid hydrolases to the endosomal pathway and are then returned from late endosomes to the trans-Golgi network (TGN) for another round of transport. The long coiled-coil protein GCC185 tethers MPR-containing vesicles at the TGN. In the second chapter of this thesis, recent progress in the study of tethers in other laboratories is reviewed. The third chapter describes a mechanism by which GCC185 may tether MPR-containing vesicles. Distinct domains required for the two known functions of this protein, maintenance of Golgi structure and tethering MPR transport vesicles, were identified. The domain needed for vesicle tethering was shown to bind the clathrin adaptor AP-1. Moreover, data are presented showing the presence of AP-1 on transport vesicles en route to the Golgi complex. These data suggest that GCC185, which is localized to the TGN through Arl1- and Rab6-GTPase binding interactions at its C-terminus, engages incoming transport vesicles by binding AP-1 via an internal coiled-coil domain near central, putative "hinge" regions of the protein. Work presented in the fourth chapter describes progress toward understanding the Golgi fragmentation phenotype of cells depleted of GCC185. In addition to the C-terminal localization domain, an N-terminal domain required for Golgi structure maintenance was identified. In addition, GCC185 binding sites for numerous Golgi-localized Rab GTPases were identified, suggesting a model in which GCC185 can make lateral connections across the Golgi ribbon in order to maintain Golgi structure or promote a fused state in the equilibrium between membrane fusion and fission characteristic of the Golgi complex.

"This brand new book discusses the most relevant technique or combination thereof for each disease and provides guidance on which modality to use -It is a disease oriented reference meant for interpreting integrated imaging studies. While it focuses on PET-CT and SPECT-CT, it also integrates PET-MR were applicable. Features: Allows clinical hybrid imaging users to compare modalities and decide whether to use PET/CT, PET/MR or SPECT/CT to solve a clinical question. Focus on clinical applications sans technological & radiopharmaceutical details. Inclusion of emerging field of PET/MR. New PART III on workflow and normal scans with various clinical tracers. Only book that incorporates PET/MR in a systematic way"--Provided by publisher.

This book focuses on the function of antibodies in vivo. Recent years have seen an exponential growth in knowledge about the molecular and cellular mechanisms of antibody activity. These new results dramatically changed our view of how antibodies function in vivo. The importance of this class of molecules is demonstrated by the heightened susceptibility to infections of humans and mice with an altered capacity to generate pathogen specific antibody responses. Thus, the majority of our currently available vaccines, such as vaccines against influenza, measles and hepatitis focus on the generation of long lasting antibody responses. Recent evidence from a variety of in vivo model systems and from human patient cohorts has highlighted the exclusive role of cellular Fc-receptors for certain immunoglobulin isotypes and subclasses. With the recent discovery of a human Fc-receptor for IgM all different human immunoglobulin isotypes now have a cellular receptor, providing a feedback mechanism and link between antibodies and the cellular components of the immune system. Moreover it has become clear the complement and Fc-receptor system are tightly connected and regulate each other to ensure a well balanced immune response. Among the immunoglobulin isotypes IgG plays a very important protective role against microbial infections and also as a therapeutic agent to kill tumor cells or autoantibody producing B cells in autoimmune disease. Transfer of our knowledge about the crucial function of Fc-receptors has led to the production of a second generation of therapeutic antibodies with enhanced binding to this class of receptors. Binding of antibodies to Fc-receptors leads to the recruitment of the potent pro-inflammatory effector functions of cells from the innate immune system. Hence, Fc-receptors link the innate and adaptive immune system, emphasizing the importance of both arms of the immune system and their crosstalk during anti-microbial immune responses. Besides this pro-inflammatory activity immunoglobulin G (IgG) molecules are long known to also have an anti-inflammatory function. This is demonstrated by the use of high dose intravenous immunoglobulins as a therapeutic agent in many human autoimmune diseases. During the past five years several new insights into the molecular and cellular pathways of this anti-inflammatory activity were gained radically changing our view of IgG function in vivo. Several lines of evidence suggest that the sugar moiety attached to the IgG molecule is responsible for these opposing activities and may be seen as a molecular switch enabling the immune system to change IgG function from a pro- to an anti-inflammatory activity. There is convincing evidence in mice and humans that aberrant IgG glycosylation could be an important new pathway for understanding the impaired antibody activity during autoimmune disease. Besides this tremendous increase in basic knowledge about factors influencing immunoglobulin activity the book will also provide insights into how these new insights might help to generate novel therapeutic approaches to enhance IgG activity for tumor therapy on the one hand, and how to block the self-destructive activity of IgG autoantibodies during autoimmune disease on the other hand.

From a structural standpoint, one of the most characteristic general design elements of the mammalian organism is its tubular nature. The lung and circulatory system shuttle oxygen and nutrients to target tissues and allow for the excretion of waste products. In some ways, the vasculature lies at the center of human physiology--its passageways provide the infrastructure for maintaining homeostasis. Despite the importance of tubular networks in human health and disease, we have a poor understanding of many aspects of the genetic, molecular, and cellular programs controlling the development of these complex structures. The Drosophila melanogaster tracheal system, an elaborate network of hollow epithelial tubes, transports gases to and from target tissues. The tracheal system, with its simple structure, tractable genetics, and substantial experimental toolkit has emerged as an excellent model system for studying questions with relevance to more complex tubular systems. During development, tracheal branches ramify on the surface of target tissues, providing oxygen to every cell in the body. However, in a phenomenon unique to the Drosophila flight muscle, trachea are also present within plasma membrane invaginations deep below the muscle's outer extremities and have been described to surround every mitochondria of the flight muscle, thus coupling oxygen delivery directly to aerobic respiration at the mitochondrion. Although the presence of trachea within flight muscle membrane invaginations has been described for over 150 years, the developmental progression and cellular and molecular basis of this subcellular targeting process is unknown. In Chapter 2, we show that tracheal branches invade the developing flight muscle Transverse (T)-tubule plasma membrane invagination system during a brief period of pupal development. Branchless (Bnl) FGF, a fibroblast growth factor that functions as a chemoattractant, is required in the flight muscle, and its cognate receptor, Breathless (Btl) FGFR, is required in trachea for the tracheal invasion process to occur. Whereas Bnl FGF is localized to all flight muscle plasma membranes prior to tracheal invasion, during invasion Bnl FGF localizes preferentially to the T-tubule and is excluded from the surrounding plasma membrane. In addition to Bnl FGF, core polarity regulators commonly found on basolateral membranes in epithelial cells also preferentially localize to the T-tubule network during tracheal invasion. We find that depletion of AP-1[gamma], targeting machinery required for basolateral secretion in Drosophila epithelia, can also reroute Bnl FGF secretion to the outer plasma membrane and away from T-tubule openings, shifting trachea to the plasma membrane and away from T-tubules. We propose that (1) polarized secretion of Bnl FGF to the T-tubule guides tracheal branches into the T-tubule network and that (2) polarized Bnl FGF secretion is established via the redeployment of ancestral basolateral secretion pathways to the T-tubules, a membrane domain having molecular signatures of epithelial basolateral domains. To our knowledge, compartmentalized secretion of Bnl FGF to flight muscle T-tubule membranes is the first example of polarized subcellular secretion of a growth factor with functional consequences for the development of another tissue. In Chapter 3, we examine the molecular machinery involved in maintaining the polarized secretion of Bnl FGF during tracheal invasion. We find a host of secretory machinery, including several Rabs, Myosin V, an actin nucleator, and others, to be involved in the secretion of Bnl-FGF to the T-tubule during tracheal invasion. From these data we propose a molecular model to explain polarized Bnl FGF secretion at the T-tubule. Why is the flight muscle the only tissue invaded by trachea? In Chapter 4, we find that the flight muscle is structurally adapted to allow its T-tubule plasma membrane invagination network to be co-opted by migrating tracheal processes. In contrast to other muscles, the flight muscle T-tubule network forms large holes on the muscle surface as part of its development. The tracheal invasion process in the flight muscle is therefore the consequence not only of a polarized secretion process as discussed in Chapter 2, but also a structurally distinct stage of flight muscle development. In the final chapter, we search for the fine tracheal tubes reported to target and form contacts on the flight muscle mitochondria. We find an extracellular protein-based lattice of the appropriate diameter and localization to potentially represent the reported tracheal extensions to the mitochondria and propose several models of protein lattice formation. We hope that insight derived from this work spurs future investigators in a host of areas. The exquisite example of targeting to specific membrane domains dependent on a subcellular chemoattractant gradient demonstrated by the invading tracheal branch may provide insight into a number of developmental scenarios where fine targeting of different cells is required. We also hope that our finding regarding polarized secretion in muscle inspires new ways to think about the assembly of muscle membranes during development and disease states.

This book provides the most up-to-date coverage of the combined use of imaging modalities in order to acquire important functional and morphological information on cardiovascular disease and enhance disease detection. The recent developments in PET/MRI, cardiac CT, PET/CT, and SPECT/CT and their impact on clinical practice are explained, and special attention is also devoted to imaging parameters and protocols for use in practice and research. The utility of multimodality imaging techniques for diagnosis and evaluation is discussed in the context of various clinical scenarios, including ischemic cardiomyopathy, myocarditis, myocardial fibrosis, cardiac sarcoidosis, and atherosclerotic plaque disease. Written by renowned researchers and clinicians, the book is an ideal concise reference on today's most advanced imaging techniques. It will appeal to all clinicians, trainees, and technicians who are involved in the diagnosis and risk assessment of cardiovascular disease.

Molecular Approach to Cancer Management discusses molecular mechanisms of cancer initiation, growth and secondary spread, emphasizing how this information can be used to devise new modes of treatment of cancer, especially in combatting secondary spread. The book addresses the basic concepts relating to cancer biology, the genetic determinants, and the signal transduction cascades associated with tumor growth, EMT, stem cell maintenance and propagation, and invasion and metastasis. The salient features of the signaling systems that are amenable to targeted manipulation are emphasized to facilitate research and development in the design of novel therapies and for the planning of new trials. This book is the only unique volume with coverage of topics that target therapy. As such, it is a valuable source for cancer researchers, molecular oncologists and members of the biomedical field who are interested in knowing more about molecular approaches to cancer therapy.

Currently, there are tremendous advances being made in understanding the basic science of both the structure and function of botulinum neurotoxins. This knowledge is opening up opportunities in regard to both therapeutic uses and treatment and protection options for civil and bio-defense applications. This volume fully evaluates the status of neurotoxin research and exploitation. The book is a multi-authored collection of chapters written by the leading authorities responsible for the current scientific and clinical research that is advancing the understanding and exploitation of the neurotoxins, and is both up to date and authoritative.

Cancer incidences increase in people living with HIV/AIDS. Over 2 million people currently live with HIV/AIDS in the US. This number will increase as HAART prolongs the average lifespan and as (at least in some states) the number of new HIV infections increase again. As this population ages their incidence rates for cancer will increase, as well. Recently, new rational targets for cancer therapy have emerged. But their application to the care of HIV+ patients is slow, because of concerns about the weakened immune status of the patients, because of possible drug interactions with HAART and because some of the AIDS defining cancer are rare.

The book describes how the balance between pro- and anti-inflammatory molecules is related to health and disease. It is suggested that many diseases are initiated and their progress is influenced by inflammatory molecules and a decrease in the production and/or action of anti-inflammatory molecules and this imbalance between pro- and anti-inflammatory molecules seems to have been initiated in the perinatal period. This implies that strategies to prevent and manage various adult diseases should start in the perinatal period. An alteration in the metaolism of essential fatty acids and their anti-inflammatory molecules such as lipoxins, resolvins, protecitns, maresins and nitrolipids seems to play a major role in the pathobiology of several adult diseases. Based on these concepts, novel therapeutic approaches in the management of insulin resistance, obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, lupus, rheumatoid arthritis and other auto-immune diseases are presented. Based on all these evidences, a unified concept that several adult diseases are due to an alteration in the balance between pro- and anti-inflammatory molecules is discussed and novel methods of their management are presented.

The gamma-proteobacterium Shewanella oneidensis MR-1 utilizes a complex electron transfer network composed primarily of c-type cytochromes as well as iron-sulfur proteins, molybdoenzymes, and flavins, to respire under anoxic conditions a variety of compounds, including fumarate, nitrate, and dimethylsulfoxide (DMSO) in addition to Fe (III) and Mn (IV) minerals. Central to several respiratory pathways in this dissimilatory metal reducing bacterium (DMRB), including the electron transfer pathway to Fe (III), is CymA, a cytoplasmic membrane-bound tetraheme c-type cytochrome that functions as the major hydroquinone dehydrogenase and couples electron transport to various periplasmic oxidoreductases. Using a genetic approach involving the reconstruction of the putative electron transport chain of dissimilatory iron reduction from Shewanella oneidensis MR-1 in Escherichia coli, I showed that expression of cymA was necessary and sufficient to convert E. coli into a dissimilatory iron reducing (DIR) bacterium, indicating that CymA as a terminal reductase was the minimal electron transport chain within S. oneidensis MR-1 to Fe (III). In addition, we isolated and characterized a [delta]cymA suppressor mutant that was capable of respiration of fumarate, ferric citrate, and DMSO, but not of nitrate. The suppression was found to be due to insertion sequence-mediated transcriptional activation of mccCD, which encode for a putative periplasmic iron sulfur protein and an integral membrane hydroquinone dehydrogenase, respectively.

"As the amount of information in biology expands dramatically, it becomes increasingly important for textbooks to distill the vast amount of scientific knowledge into concise principles and enduring concepts. As with previous editions, Molecular Biology of the Cell, Sixth Edition accomplishes this goal with clear writing and beautiful illustrations. The Sixth Edition has been extensively revised and updated with the latest research in the field of cell biology, and it provides an exceptional framework for teaching and learning. The entire illustration program has been greatly enhanced. Protein structures better illustrate structure-function relationships, icons are simpler and more consistent within and between chapters, and micrographs have been refreshed and updated with newer, clearer, or better images. As a new feature, each chapter now contains intriguing open-ended questions highlighting "What We Don't Know," introducing students to challenging areas of future research. Updated end-of-chapter problems reflect new research discussed in the text. Thought-provoking end-of-chapter questions have been expanded to all chapters, including questions on developmental biology, tissues and stem cells, the immune system, and pathogens."-- Provided by publisher.

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